KR20210114967A - 신규 치환된 설포닐우레아 유도체 - Google Patents
신규 치환된 설포닐우레아 유도체 Download PDFInfo
- Publication number
- KR20210114967A KR20210114967A KR1020217025116A KR20217025116A KR20210114967A KR 20210114967 A KR20210114967 A KR 20210114967A KR 1020217025116 A KR1020217025116 A KR 1020217025116A KR 20217025116 A KR20217025116 A KR 20217025116A KR 20210114967 A KR20210114967 A KR 20210114967A
- Authority
- KR
- South Korea
- Prior art keywords
- carbamoyl
- hexahydro
- indacen
- ethene
- sulfonamide
- Prior art date
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- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 238000000034 method Methods 0.000 claims abstract description 43
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 claims abstract description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 239000003112 inhibitor Substances 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 102000003777 Interleukin-1 beta Human genes 0.000 claims abstract description 12
- 108090000193 Interleukin-1 beta Proteins 0.000 claims abstract description 12
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 claims abstract description 10
- 230000000694 effects Effects 0.000 claims abstract description 8
- JOXWSDNHLSQKCC-UHFFFAOYSA-N ethenesulfonamide Chemical compound NS(=O)(=O)C=C JOXWSDNHLSQKCC-UHFFFAOYSA-N 0.000 claims description 77
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 71
- -1 C 1 -C 6 alkoxy Chemical group 0.000 claims description 65
- 229940124530 sulfonamide Drugs 0.000 claims description 54
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 44
- 239000011734 sodium Substances 0.000 claims description 44
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 40
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 35
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 claims description 29
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 229920002554 vinyl polymer Polymers 0.000 claims description 26
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 229910005965 SO 2 Inorganic materials 0.000 claims description 23
- 150000001408 amides Chemical class 0.000 claims description 21
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 15
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 150000003573 thiols Chemical class 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 150000007942 carboxylates Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- YKRLMZKCVQTOAZ-NSCUHMNNSA-N (e)-prop-1-ene-1-sulfonamide Chemical compound C\C=C\S(N)(=O)=O YKRLMZKCVQTOAZ-NSCUHMNNSA-N 0.000 claims description 6
- DXKGICMXRZOUDL-FERCGXDMSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(oxan-4-yl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)C1CCOCC1 DXKGICMXRZOUDL-FERCGXDMSA-N 0.000 claims description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 102000003810 Interleukin-18 Human genes 0.000 claims description 6
- 108090000171 Interleukin-18 Proteins 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 150000003456 sulfonamides Chemical class 0.000 claims description 5
- JHWUNBMMLDCHCY-CDIAOGBUSA-N tert-butyl (2S)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C JHWUNBMMLDCHCY-CDIAOGBUSA-N 0.000 claims description 5
- 125000004001 thioalkyl group Chemical group 0.000 claims description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- WYNYJDQVSFSVSM-ZRDIBKRKSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-(1-methylsulfonylpiperidin-3-yl)ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1CN(CCC1)S(=O)(=O)C WYNYJDQVSFSVSM-ZRDIBKRKSA-N 0.000 claims description 3
- MZVATKUUYWKXIY-PKNBQFBNSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-(oxolan-2-yl)ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1OCCC1 MZVATKUUYWKXIY-PKNBQFBNSA-N 0.000 claims description 3
- YFGGGFLYGJADIC-FHLIRTJZSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(1,3-thiazol-2-ylmethyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)CC=1SC=CN=1 YFGGGFLYGJADIC-FHLIRTJZSA-N 0.000 claims description 3
- COLOGWRYSWXUTA-PMXLPMHFSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)CCOC COLOGWRYSWXUTA-PMXLPMHFSA-N 0.000 claims description 3
- INKVOZKPRLXZJO-XSSIKURBSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(2-methylpropyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)CC(C)C INKVOZKPRLXZJO-XSSIKURBSA-N 0.000 claims description 3
- GKGZPDSWYKRGBQ-PMXLPMHFSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(2-methylsulfanylethyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)CCSC GKGZPDSWYKRGBQ-PMXLPMHFSA-N 0.000 claims description 3
- DQGIUKSJWPQQPX-QXLXQBSBSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(oxetan-3-yl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)C1COC1 DQGIUKSJWPQQPX-QXLXQBSBSA-N 0.000 claims description 3
- YPMLXTSZWOTFEF-FERCGXDMSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(thian-4-yl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)C1CCSCC1 YPMLXTSZWOTFEF-FERCGXDMSA-N 0.000 claims description 3
- CYDPFUHPFRLLLI-YFPIXMDGSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-(thiophene-3-carbonyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)C(=O)C1=CSC=C1 CYDPFUHPFRLLLI-YFPIXMDGSA-N 0.000 claims description 3
- NYKFGKSJMMMIPM-YBHKSSGVSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-methylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)C NYKFGKSJMMMIPM-YBHKSSGVSA-N 0.000 claims description 3
- DLMXPEWPOFUJGO-YBHKSSGVSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-methylsulfonylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)S(=O)(=O)C DLMXPEWPOFUJGO-YBHKSSGVSA-N 0.000 claims description 3
- BOUHGSBHZUOHHX-IYPOZPNPSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-propan-2-ylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)C(C)C BOUHGSBHZUOHHX-IYPOZPNPSA-N 0.000 claims description 3
- TXXKJKWMKOTGRT-IYPOZPNPSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-propan-2-ylsulfonylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound CC(C)S(N(CCC1)[C@H]1/C=C/S(NC(NC1=C(CCC2)C2=CC2=C1CCC2)=O)(=O)=O)(=O)=O TXXKJKWMKOTGRT-IYPOZPNPSA-N 0.000 claims description 3
- XKUYBFASGLGXEA-GPZRYRNASA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-1-propylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)CCC XKUYBFASGLGXEA-GPZRYRNASA-N 0.000 claims description 3
- DEHGPTYMCGLXHE-SWDTZWKESA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-2-methyl-1-(2-methylpropyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@]1(N(CCC1)CC(C)C)C DEHGPTYMCGLXHE-SWDTZWKESA-N 0.000 claims description 3
- HWZNPBNCJQSGBO-ZOXUKVPXSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-2-methyl-1-methylsulfonylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C[C@@](CCC1)(/C=C/S(NC(NC2=C(CCC3)C3=CC3=C2CCC3)=O)(=O)=O)N1S(C)(=O)=O HWZNPBNCJQSGBO-ZOXUKVPXSA-N 0.000 claims description 3
- CCRYUSZLTXBJGF-ZAHGZRRWSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2R)-2-methylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@]1(NCCC1)C CCRYUSZLTXBJGF-ZAHGZRRWSA-N 0.000 claims description 3
- XRAVZCGWAFRMHQ-VEMDQMBVSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2S)-1-(1,3-thiazol-2-yl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@H]1N(CCC1)C=1SC=CN=1 XRAVZCGWAFRMHQ-VEMDQMBVSA-N 0.000 claims description 3
- JZCKBJJWOPVKSK-VEMDQMBVSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2S)-1-(2-hydroxyethyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@H]1N(CCC1)CCO JZCKBJJWOPVKSK-VEMDQMBVSA-N 0.000 claims description 3
- JPLOFCGEICYQCW-RNTFSAEZSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2S)-1-(oxane-4-carbonyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@H]1N(CCC1)C(=O)C1CCOCC1 JPLOFCGEICYQCW-RNTFSAEZSA-N 0.000 claims description 3
- ASVKRQZKXFJCEI-VUVZNRFTSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2S)-1-(thiophen-2-ylmethyl)pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@H]1N(CCC1)CC=1SC=CC=1 ASVKRQZKXFJCEI-VUVZNRFTSA-N 0.000 claims description 3
- CCRYUSZLTXBJGF-XETPZZHUSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[(2S)-2-methylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@]1(NCCC1)C CCRYUSZLTXBJGF-XETPZZHUSA-N 0.000 claims description 3
- WTPNDFSJDZYQAM-GXDHUFHOSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[2-methyl-1-(2-methylsulfanylethyl)azetidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1(N(CC1)CCSC)C WTPNDFSJDZYQAM-GXDHUFHOSA-N 0.000 claims description 3
- MNYNDLQPNMRALC-PKNBQFBNSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-[2-methyl-1-(oxetan-3-yl)azetidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1(N(CC1)C1COC1)C MNYNDLQPNMRALC-PKNBQFBNSA-N 0.000 claims description 3
- RNAZCPXMLHAHDQ-ZRDIBKRKSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-piperidin-2-ylethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1NCCCC1 RNAZCPXMLHAHDQ-ZRDIBKRKSA-N 0.000 claims description 3
- YUWZXGCVUUTWGF-PKNBQFBNSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-piperidin-3-ylethenyl]sulfonylurea Chemical class C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1CNCCC1 YUWZXGCVUUTWGF-PKNBQFBNSA-N 0.000 claims description 3
- DEQBNVAZYJLALD-CSKARUKUSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-2-pyrrolidin-3-ylethenyl]sulfonylurea Chemical class C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1CNCC1 DEQBNVAZYJLALD-CSKARUKUSA-N 0.000 claims description 3
- SOYGCYGEQFYJCC-WLRTZDKTSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(E)-3-piperidin-2-ylprop-1-enyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\CC1NCCCC1 SOYGCYGEQFYJCC-WLRTZDKTSA-N 0.000 claims description 3
- NYKFGKSJMMMIPM-UILAEWCASA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(Z)-2-[(2R)-1-methylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C/[C@@H]1N(CCC1)C NYKFGKSJMMMIPM-UILAEWCASA-N 0.000 claims description 3
- BOUHGSBHZUOHHX-FWFZHJKVSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[(Z)-2-[(2R)-1-propan-2-ylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C/[C@@H]1N(CCC1)C(C)C BOUHGSBHZUOHHX-FWFZHJKVSA-N 0.000 claims description 3
- VWOICPGJDYFEBR-ZRDIBKRKSA-N 1-(1,2,3,6,7,8-hexahydro-as-indacen-4-yl)-3-[(E)-2-(1-methylsulfonylpyrrolidin-2-yl)ethenyl]sulfonylurea Chemical compound C1CCC2=C(C=C3CCCC3=C12)NC(=O)NS(=O)(=O)\C=C\C1N(CCC1)S(=O)(=O)C VWOICPGJDYFEBR-ZRDIBKRKSA-N 0.000 claims description 3
- KBBNZPGYZXSRQQ-PYDKSLIFSA-N 1-(1,2,3,6,7,8-hexahydro-as-indacen-4-yl)-3-[(E)-2-[(2R)-2-methylpyrrolidin-2-yl]ethenyl]sulfonylurea 2,2,2-trifluoroacetic acid Chemical compound FC(C(=O)O)(F)F.C1CCC2=C(C=C3CCCC3=C12)NC(=O)NS(=O)(=O)\C=C\[C@@]1(NCCC1)C KBBNZPGYZXSRQQ-PYDKSLIFSA-N 0.000 claims description 3
- KBBNZPGYZXSRQQ-SURWLETJSA-N 1-(1,2,3,6,7,8-hexahydro-as-indacen-4-yl)-3-[(E)-2-[(2S)-2-methylpyrrolidin-2-yl]ethenyl]sulfonylurea 2,2,2-trifluoroacetic acid Chemical compound FC(C(=O)O)(F)F.C1CCC2=C(C=C3CCCC3=C12)NC(=O)NS(=O)(=O)\C=C\[C@]1(NCCC1)C KBBNZPGYZXSRQQ-SURWLETJSA-N 0.000 claims description 3
- RLEMYJJQVIUISZ-VAWYXSNFSA-N 1-[(E)-2-(2,3-dihydro-1H-indol-2-yl)ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical class C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)\C=C\C1NC2=CC=CC=C2C1 RLEMYJJQVIUISZ-VAWYXSNFSA-N 0.000 claims description 3
- ZQRQIKILCMNYOC-CSKARUKUSA-N 1-[(E)-2-(azetidin-2-yl)ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical class N1C(CC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O ZQRQIKILCMNYOC-CSKARUKUSA-N 0.000 claims description 3
- ODCRBOKHJUZMFO-ZSKDKACUSA-N 1-[(E)-2-[(2R)-1,1-diethyl-2-methylpyrrolidin-1-ium-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea bromide Chemical compound [Br-].C(C)[N+]1([C@@](CCC1)(C)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O)CC ODCRBOKHJUZMFO-ZSKDKACUSA-N 0.000 claims description 3
- TZLKYCQVBHHRML-ZISLFAKRSA-N 1-[(E)-2-[(2R)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-3-[2,6-di(propan-2-yl)phenyl]urea Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@@]1(N(CCC1)C)C TZLKYCQVBHHRML-ZISLFAKRSA-N 0.000 claims description 3
- LVPKXOUNYJLRPL-JTGXYLHZSA-N 1-[(E)-2-[(2R)-1-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea 2,2,2-trifluoroacetic acid Chemical compound FC(C(=O)O)(F)F.C1CCC2=C(C=3CCCC3C=C12)NC(=O)NS(=O)(=O)\C=C\[C@@H]1N(CCC1)C1CC2C(CNC2)C1 LVPKXOUNYJLRPL-JTGXYLHZSA-N 0.000 claims description 3
- QZHDWHIURRRQOU-IYPOZPNPSA-N 1-[(E)-2-[(2R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C1(CC1)C(=O)N1[C@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O QZHDWHIURRRQOU-IYPOZPNPSA-N 0.000 claims description 3
- PNXQTJMUCZEVEI-DGWAXEAPSA-N 1-[(E)-2-[(2R)-1-cyclohexylpyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C1(CCCCC1)N1[C@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O PNXQTJMUCZEVEI-DGWAXEAPSA-N 0.000 claims description 3
- GTYJNCXJRHVURF-KETLNSEPSA-N 1-[(E)-2-[(2R)-1-cyclohexylsulfonylpyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C1(CCCCC1)S(=O)(=O)N1[C@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O GTYJNCXJRHVURF-KETLNSEPSA-N 0.000 claims description 3
- TZLKYCQVBHHRML-OSJHKOOESA-N 1-[(E)-2-[(2S)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-3-[2,6-di(propan-2-yl)phenyl]urea Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@]1(N(CCC1)C)C TZLKYCQVBHHRML-OSJHKOOESA-N 0.000 claims description 3
- WECPQYKPWZDTKV-RPAADVPWSA-N 1-[(E)-2-[(2S)-1-(3H-benzimidazole-5-carbonyl)pyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound N1C=NC2=C1C=C(C=C2)C(=O)N1[C@@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O WECPQYKPWZDTKV-RPAADVPWSA-N 0.000 claims description 3
- QZWQOORIYFSBCT-HVJHFUJKSA-N 1-[(E)-2-[(2S)-1-(5-chlorothiophen-2-yl)sulfonylpyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound ClC1=CC=C(S1)S(=O)(=O)N1[C@@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O QZWQOORIYFSBCT-HVJHFUJKSA-N 0.000 claims description 3
- DHSCPBFMMZQVQZ-JLQMKUNGSA-N 1-[(E)-2-[(2S)-1-[(4-cyanophenyl)methyl]pyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C(#N)C1=CC=C(CN2[C@@H](CCC2)/C=C/S(=O)(=O)NC(NC2=C3CCCC3=CC=3CCCC2=3)=O)C=C1 DHSCPBFMMZQVQZ-JLQMKUNGSA-N 0.000 claims description 3
- ABYMRFCYEYTLMM-HVJHFUJKSA-N 1-[(E)-2-[(2S)-1-acetylpyrrolidin-2-yl]ethenyl]sulfonyl-3-[2,6-di(propan-2-yl)phenyl]urea Chemical compound C(C)(=O)N1[C@@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C(C=CC=C1C(C)C)C(C)C)=O ABYMRFCYEYTLMM-HVJHFUJKSA-N 0.000 claims description 3
- RJKMTCXPGFQVAL-HVJHFUJKSA-N 1-[(E)-2-[(2S)-1-cyclopropylsulfonylpyrrolidin-2-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea Chemical compound C1(CC1)S(=O)(=O)N1[C@@H](CCC1)/C=C/S(=O)(=O)NC(NC1=C2CCCC2=CC=2CCCC1=2)=O RJKMTCXPGFQVAL-HVJHFUJKSA-N 0.000 claims description 3
- MYJFGHDVCREYQA-OFWRTZPDSA-N 1-[(E)-2-[(3R)-1,1-diethylpyrrolidin-1-ium-3-yl]ethenyl]sulfonyl-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea bromide Chemical compound [Br-].C(C)[N+]1(C[C@H](CC1)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O)CC MYJFGHDVCREYQA-OFWRTZPDSA-N 0.000 claims description 3
- QOJGUIWYHPVDES-VSOYFRJCSA-N 1-[2,6-di(propan-2-yl)phenyl]-3-[(E)-2-[(2S)-1-ethylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@H]1N(CCC1)CC QOJGUIWYHPVDES-VSOYFRJCSA-N 0.000 claims description 3
- OICVIFBHFPCTRV-BYIUCRAPSA-N 1-[2,6-di(propan-2-yl)phenyl]-3-[(E)-2-[(2S)-1-methylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@H]1N(CCC1)C OICVIFBHFPCTRV-BYIUCRAPSA-N 0.000 claims description 3
- FCXGLZSGGMVABT-BYIUCRAPSA-N 1-[2,6-di(propan-2-yl)phenyl]-3-[(E)-2-[(2S)-1-methylsulfonylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@H]1N(CCC1)S(=O)(=O)C FCXGLZSGGMVABT-BYIUCRAPSA-N 0.000 claims description 3
- JOQRNZFJIFAOKC-PABFRNLHSA-N 1-[2,6-di(propan-2-yl)phenyl]-3-[(E)-2-[(2S)-pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@H]1NCCC1 JOQRNZFJIFAOKC-PABFRNLHSA-N 0.000 claims description 3
- BFIGZBZWKFPOHQ-DZZUKKPASA-N 1-[4-fluoro-2,6-di(propan-2-yl)phenyl]-3-[(E)-2-[(2S)-1-methylpyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound CC(C)C1=CC(=CC(=C1NC(=O)NS(=O)(=O)/C=C/[C@@H]2CCCN2C)C(C)C)F BFIGZBZWKFPOHQ-DZZUKKPASA-N 0.000 claims description 3
- GIXKEBKLGHRKJE-OHNBSPBNSA-N 1-[4-fluoro-2,6-di(propan-2-yl)phenyl]-3-[(E)-2-[(2S)-2-methylpyrrolidin-2-yl]ethenyl]sulfonylurea 2,2,2-trifluoroacetic acid Chemical compound FC(C(=O)O)(F)F.FC1=CC(=C(C(=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@]1(NCCC1)C)C(C)C GIXKEBKLGHRKJE-OHNBSPBNSA-N 0.000 claims description 3
- CHAXJZZVFOENHD-HEWZJLJBSA-N 1-[4-fluoro-2,6-di(propan-2-yl)phenyl]-3-[(E)-2-[(2S)-pyrrolidin-2-yl]ethenyl]sulfonylurea Chemical compound FC1=CC(=C(C(=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@H]1NCCC1)C(C)C CHAXJZZVFOENHD-HEWZJLJBSA-N 0.000 claims description 3
- TYHYESDUJZRBKS-UHFFFAOYSA-N 2,3-dihydroindole-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)CCC2=C1 TYHYESDUJZRBKS-UHFFFAOYSA-N 0.000 claims description 3
- MVEXISNMHAYAHC-QIXNEVBVSA-N C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)C(=O)OC(C)(C)C Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)C(=O)OC(C)(C)C MVEXISNMHAYAHC-QIXNEVBVSA-N 0.000 claims description 3
- JSRVSTAILAGIPG-WHTNWRSGSA-N FC(C(=O)O)(F)F.C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@@]1(NCCC1)C Chemical compound FC(C(=O)O)(F)F.C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@@]1(NCCC1)C JSRVSTAILAGIPG-WHTNWRSGSA-N 0.000 claims description 3
- JSRVSTAILAGIPG-CTZWGZJRSA-N FC(C(=O)O)(F)F.C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@]1(NCCC1)C Chemical compound FC(C(=O)O)(F)F.C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)\C=C\[C@]1(NCCC1)C JSRVSTAILAGIPG-CTZWGZJRSA-N 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
- 239000010977 jade Substances 0.000 claims description 3
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 claims description 3
- 230000011664 signaling Effects 0.000 claims description 3
- HWGCTLVXBZCGHR-SMLPRVBWSA-M sodium 1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl-[(E)-2-[(2R)-1-(thian-4-yl)pyrrolidin-2-yl]ethenyl]sulfonylazanide Chemical compound O=C([N-]S(/C=C/[C@@H](CCC1)N1C1CCSCC1)(=O)=O)NC1=C(CCC2)C2=CC2=C1CCC2.[Na+] HWGCTLVXBZCGHR-SMLPRVBWSA-M 0.000 claims description 3
- BGUQSGNAZKLTNG-LCDZROKASA-M sodium [(E)-2-[(2R)-1-cyclohexylpyrrolidin-2-yl]ethenyl]sulfonyl-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)azanide Chemical compound C1(CCCCC1)N1[C@H](CCC1)/C=C/S(=O)(=O)[N-]C(NC1=C2CCCC2=CC=2CCCC1=2)=O.[Na+] BGUQSGNAZKLTNG-LCDZROKASA-M 0.000 claims description 3
- ZURLJICOPSQYSG-XKKCTYCISA-M sodium [(E)-2-[(2S)-1,2-dimethylpyrrolidin-2-yl]ethenyl]sulfonyl-[[2,6-di(propan-2-yl)phenyl]carbamoyl]azanide Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)[N-]S(=O)(=O)\C=C\[C@]1(N(CCC1)C)C.[Na+] ZURLJICOPSQYSG-XKKCTYCISA-M 0.000 claims description 3
- QVYOEJKNXRYRTF-LWEBZGTRSA-M sodium [(E)-2-[(2S)-1-ethylpyrrolidin-2-yl]ethenyl]sulfonyl-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)azanide Chemical compound C(C)N1[C@@H](CCC1)/C=C/S(=O)(=O)[N-]C(NC1=C2CCCC2=CC=2CCCC1=2)=O.[Na+] QVYOEJKNXRYRTF-LWEBZGTRSA-M 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- JHWUNBMMLDCHCY-IVYUTVGYSA-N tert-butyl (2R)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C JHWUNBMMLDCHCY-IVYUTVGYSA-N 0.000 claims description 3
- RYHNWVFHZCXDTA-IVYUTVGYSA-N tert-butyl (2R)-2-[(E)-2-(1,2,3,6,7,8-hexahydro-as-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CCC1)[C@@]1(C)/C=C/S(NC(NC1=C(CCC2)C2=C(CCC2)C2=C1)=O)(=O)=O)=O RYHNWVFHZCXDTA-IVYUTVGYSA-N 0.000 claims description 3
- CTFPPBJDIWQIGK-SXKZTFQGSA-N tert-butyl (2R)-2-[(E)-2-[[2,6-di(propan-2-yl)phenyl]carbamoylsulfamoyl]ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C CTFPPBJDIWQIGK-SXKZTFQGSA-N 0.000 claims description 3
- RYHNWVFHZCXDTA-CDIAOGBUSA-N tert-butyl (2S)-2-[(E)-2-(1,2,3,6,7,8-hexahydro-as-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C1CCC2=C(C=C3CCCC3=C12)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C RYHNWVFHZCXDTA-CDIAOGBUSA-N 0.000 claims description 3
- CTFPPBJDIWQIGK-YVIRBKRRSA-N tert-butyl (2S)-2-[(E)-2-[[2,6-di(propan-2-yl)phenyl]carbamoylsulfamoyl]ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C CTFPPBJDIWQIGK-YVIRBKRRSA-N 0.000 claims description 3
- JOBPHUXYUNDTCM-BVYAJCBJSA-N tert-butyl (2S)-2-[(E)-2-[[4-fluoro-2,6-di(propan-2-yl)phenyl]carbamoylsulfamoyl]ethenyl]-2-methylpyrrolidine-1-carboxylate Chemical compound FC1=CC(=C(C(=C1)C(C)C)NC(=O)NS(=O)(=O)/C=C/[C@]1(N(CCC1)C(=O)OC(C)(C)C)C)C(C)C JOBPHUXYUNDTCM-BVYAJCBJSA-N 0.000 claims description 3
- XULFFLKHTKMKRJ-FPBAGDOUSA-N tert-butyl (2S)-2-ethyl-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]pyrrolidine-1-carboxylate Chemical compound C(C)[C@@]1(N(CCC1)C(=O)OC(C)(C)C)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O XULFFLKHTKMKRJ-FPBAGDOUSA-N 0.000 claims description 3
- CSYBHVSNENPHSJ-WYMLVPIESA-N tert-butyl 2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1(N(CC1)C(=O)OC(C)(C)C)C CSYBHVSNENPHSJ-WYMLVPIESA-N 0.000 claims description 3
- XPTHVLBBFHGHBZ-ACCUITESSA-N tert-butyl 2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]azetidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(CC1)\C=C\S(NC(NC1=C2CCCC2=CC=2CCCC1=2)=O)(=O)=O XPTHVLBBFHGHBZ-ACCUITESSA-N 0.000 claims description 3
- INIVLSGSRUGPKX-WYMLVPIESA-N tert-butyl 3-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]piperidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1CN(CCC1)C(=O)OC(C)(C)C INIVLSGSRUGPKX-WYMLVPIESA-N 0.000 claims description 3
- MRYRWKZDFKTCAZ-NTCAYCPXSA-N tert-butyl 4-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]piperidine-1-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1CCN(CC1)C(=O)OC(C)(C)C MRYRWKZDFKTCAZ-NTCAYCPXSA-N 0.000 claims description 3
- VDCWMCUZOOQMOA-HVJYDRJSSA-N tert-butyl 5-[(2R)-2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]pyrrolidin-1-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/[C@@H]1N(CCC1)C1CC2C(CN(C2)C(=O)OC(C)(C)C)C1 VDCWMCUZOOQMOA-HVJYDRJSSA-N 0.000 claims description 3
- ZGDFDQGZWMHCOD-GHRIWEEISA-N tert-butyl N-[2-[2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidin-1-yl]ethyl]-N-methylcarbamate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1(N(CC1)CCN(C(OC(C)(C)C)=O)C)C ZGDFDQGZWMHCOD-GHRIWEEISA-N 0.000 claims description 3
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- TVOUVSXGMVEREH-NBVRZTHBSA-N tert-butyl N-[3-[2-[(E)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoylsulfamoyl)ethenyl]-2-methylazetidin-1-yl]propyl]-N-methylcarbamate Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)/C=C/C1(N(CC1)CCCN(C(OC(C)(C)C)=O)C)C TVOUVSXGMVEREH-NBVRZTHBSA-N 0.000 claims description 3
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- NIASXSNPLHNDKA-JGAIRUGNSA-N tert-butyl (2R)-2-[(Z)-2-sulfamoylethenyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CCC1)[C@H]1/C=C\S(N)(=O)=O)=O NIASXSNPLHNDKA-JGAIRUGNSA-N 0.000 description 1
- AHXRXGFJKWRVIZ-DPCFLFMUSA-N tert-butyl (2R)-2-methyl-2-[(E)-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]ethenyl]pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@]1(N(CCC1)C(=O)OC(C)(C)C)C AHXRXGFJKWRVIZ-DPCFLFMUSA-N 0.000 description 1
- NIASXSNPLHNDKA-ORZBULNSSA-N tert-butyl (2S)-2-[(E)-2-sulfamoylethenyl]pyrrolidine-1-carboxylate Chemical compound S(N)(=O)(=O)/C=C/[C@H]1N(CCC1)C(=O)OC(C)(C)C NIASXSNPLHNDKA-ORZBULNSSA-N 0.000 description 1
- NIASXSNPLHNDKA-XZLDQRQTSA-N tert-butyl (2S)-2-[(Z)-2-sulfamoylethenyl]pyrrolidine-1-carboxylate Chemical compound S(N)(=O)(=O)\C=C/[C@H]1N(CCC1)C(=O)OC(C)(C)C NIASXSNPLHNDKA-XZLDQRQTSA-N 0.000 description 1
- AHXRXGFJKWRVIZ-JICACKBISA-N tert-butyl (2S)-2-methyl-2-[(E)-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]ethenyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(NS(/C=C/[C@](C)(CCC1)N1C(OC(C)(C)C)=O)(=O)=O)=O AHXRXGFJKWRVIZ-JICACKBISA-N 0.000 description 1
- AJDUUXDKGPLRNS-CSKARUKUSA-N tert-butyl 2-[(E)-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]ethenyl]azetidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)NS(=O)(=O)/C=C/C1N(CC1)C(=O)OC(C)(C)C AJDUUXDKGPLRNS-CSKARUKUSA-N 0.000 description 1
- KKYOFGBBPXDNGX-SOFGYWHQSA-N tert-butyl 2-methyl-2-[(E)-2-sulfamoylethenyl]azetidine-1-carboxylate Chemical compound CC1(N(CC1)C(=O)OC(C)(C)C)\C=C\S(N)(=O)=O KKYOFGBBPXDNGX-SOFGYWHQSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
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- C07D207/48—Sulfur atoms
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
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Abstract
본 발명은 일반식 (I)의 신규 헤테로시클릭 화합물, 이의 약학적으로 허용가능한 염, 약학적으로 허용가능한 용매화물, 거울상이성질체, 부분입체이성질체 및 다형체에 관한 것이다. 본 발명은 또한 본 발명의 화합물을 제조하는 방법, 상기 화합물을 함유하는 약학적 조성물, 및 NOD-유사 수용체 패밀리 (NLR) 단백질 NLRP3 조절제의 패밀리에 속하는 본 발명의 화합물로서의 이들의 용도에 관한 것이다. 따라서, 본 발명은 신규 NLRP3 조절제에 관한 것뿐만 아니라 인터루킨 1β 활성이 연루된 질병 또는 상태의 치료에서 신규 억제제 화합물의 용도에 관한 것이다.
식 (I)
식 (I)
Description
본 발명은 일반식 (I)의 신규 헤테로시클릭 화합물, 이의 약학적으로 허용가능한 염, 약학적으로 허용가능한 용매화물, 거울상이성질체, 부분입체이성질체 및 다형체에 관한 것이다. 본 발명은 또한 본 발명의 화합물을 제조하는 방법, 상기 화합물을 함유하는 약학적 조성물, 및 NOD-유사 수용체 패밀리 (NLR) 단백질 NLRP3 조절제의 패밀리에 속하는 본 발명의 화합물로서의 이들의 용도에 관한 것이다. 따라서, 본 발명은 신규 NLRP3 조절제에 관한 것뿐만 아니라 인터루킨 1β 활성이 연루된 질병 또는 상태의 치료에서 신규 억제제 화합물의 용도에 관한 것이다.
NOD-유사 수용체 패밀리 (NOD-like receptor family, NLR) 단백질 NLRP3은 많은 병원체, 환경 및 숙주 유래 요인을 감지하는 세포내 신호전달 분자이다. (Wen., et. al., Immunity. 2013; 39:432-441). NLRP3의 활성화는 CARD를 함유하는 세포사멸 연관 speck-유사 단백질(apoptosis associated speck-like protein containing a CARD, ASC)과의 결합을 야기한다. ASC는 차례로 시스테인 프로테아제 카스파제-1과 상호작용하여, 염증소체(inflammasome)라는 복합체를 형성한다. 그 결과 카스파제-1이 활성화되는데, 이는 전염증성 사이토카인 IL-1β 및 IL-18을 이들의 활성 형태로 절단하고, 파이롭토시스(pyroptosis)로 알려진 일종의 염증성 세포 사멸을 매개한다. 다른 세포내 패턴 인식 수용체(pattern recognition receptor, PRR)들도 염증소체를 형성할 수 있다. 이들은 다른 NLR 패밀리 멤버, 예컨대 NLRP1 및 NLRC4, 및 비-NLR PRR, 예컨대 이중가닥 DNA (dsDNA) 센서 AIM2(absent in melanoma 2) 및 인터페론, 감마 유도성 단백질 16 (IFI16)을 포함한다(Latz, et. al., Nat Rev Immunol. 2013; 13:397-411). NLRP3-의존성 IL-1β 프로세싱은 또한 카스파제-1의 간접적인 비정규 경로 다운스트림에 의해 활성화될 수 있다(Lamkanfi, et. al., Cell. 2014; 157:1013-1022).
염증소체 구성요소, 예컨대 NLRP3, ASC 및 카스파제-1은 Kupffer 세포, 침윤성 대식세포, 간세포 및 간 성상 세포를 포함하는 간의 면역 세포에서 발현된다. 염증소체 활성화는 두 개의 연속 신호에 의존한다. 신호 1은 TLR 및 IL-1R 신호전달에 의해 구동되며, NLRP3, ASC, 전-카스파제-1, 전-IL-1β, 및 전-IL-18를 포함하는 구성 단백질의 발현을 포함한다. 신호 2는 NASH 발달 동안 스트레스에 의해 또는 죽어가는 간세포에 의해 또는 “새는(leaky)” 장 (PAMPs)을 통해 주로 방출되는 위험 신호(danger signals, DAMPS)에 의해 제공된다. 이 과정은 염증소체 구성요소의 올리고머화 및 전-카스파제-1의 절단으로 이어져, 활성 전염증성 사이토카인의 방출을 야기한다.
NLRP3 염증소체는 전염증성 사이토카인 인터루킨-1β (IL-1β) 및 인터루킨-18 (IL-18)의 처리 및 방출을 야기하는 카스파제-1의 활성화를 통해 염증 반응의 핵심 매개체로 작용한다. NLRP3 염증소체는 염증 과정의 구성요소이며, 이의 비정상적인 활성화는 유전 장애, 예컨대 희귀 주기성 열 증후군(rare periodic fever syndrome), 크리오피린 연관 주기성 증후군(cryopyrin associated periodic syndromes, CAPS), 종양 괴사인자 수용체 연관 주기성 증후군(Tumor necrosis factor receptor-associated periodic syndrome, TRAPS) 및 복합 질병, 예컨대 다발성 경화증, 염증성 장질환(Inflammatory bowel disease, IBD), 제2형 당뇨병, 죽상동맥경화증, 천식, 통풍성 관절염, 및 파킨슨병, 알츠하이머병과 기타 뇌 질병을 포함하는 염증성 중추신경계(CNS) 질병에서 병원성이다. (Masters, et. al., Annu Rev Immunol. 2009; 27:621-668; Strowig, et. al., Nature 2012, 481, 278-286; Guo, et. al., Nat. Med. 2015, 21, 677; Ising, et.al., Nature 2019, 575, 669-673.)
염증은 감염 및 손상에 대한 필수적인 숙주 반응이다. 감염에 대한 숙주 반응의 중심인 전염증성 사이토카인 인터루킨-1β (IL-1β)의 조절은, 또한 부적절하게 활성화될 때 조직 손상을 유발한다. (Dinarello, et. al., Nat. Rev. Drug Discovery 2012, 11, 633-652.) NLRP3 염증소체 활성화는 전염증성 신호전달의 유도, 간세포 손상 및 세포 사멸, 및 콜라겐 침착 및 간 섬유증에 책임이 있는 간 성상 세포 (HSC)의 활성화를 포함하는 각각의 구성요소에서 핵심적인 역할을 한다. 특히, NAFLD에서 NASH로의 전환은 NLRP3-염증소체 활성화 및 ASC (apoptosis-associated speck-like protein containing a carboxy-terminal CARD), 카스파제-1 (CASP-1)과 판넥신을 포함하는 염증소체-관련 구성요소의 증가된 발현과 연관된다. (Mridha, et. al., Journal of Hepatology, 2017, 66 (5), 1037-1046)
NLRP3 관련 질병에 대한 현재 치료법은 IL-1을 표적으로 하는 생물학적 제제를 포함한다. 이들은 재조합 IL-1 수용체 길항체 아나킨라(Anakinra), 중화 IL-1β 항체 카나키누맙(Canakinumab) 및 가용성 유인 IL-1 수용체 리로나셉트(Rilonacep)이다.
Wipo 특허 출원 WO98/32733, WO2001/019390, WO2014/190015, WO2016/123229 WO2016/131098는 NLRP3 염증소체 억제제로서의 설포닐우레아 유도체 및 관련 화합물들을 개시하고 있다. WO2017/017469는 인터루킨 1β 활성이 연루된 질병 또는 상태의 치료를 위한 NLRP3 염증소체 억제제로서의 특정 시클릭 디아릴보론 유도체를 개시하고 있다. 일부 최근 특허 출원, 예컨대 WO2017/031161, WO2017/079352, WO2017/129897, WO2017/184623, WO2018/225018, WO2019/043610, WO2019/023147, WO2019/008029, WO2019/068772도 NLRP3 억제제로서의 특정 부류의 화합물들을 개시하고 있다.
본 발명자들은 본원에서 NLRP3 경로를 통해 매개되는, 염증, 크리오피린 연관 주기성 증후군(CAPS), 통풍성 관절염, 다발성 경화증, 염증성 장질환(IBD), 제2형 당뇨병, 죽상동맥경화증, 간 섬유증 염증성 중추신경계(CNS) 질병, 예컨대 파킨슨병, 알츠하이머병 및 기타 뇌 질병을 포함하는, NLRP3에 의해 매개된 질병 상태 또는 인터루킨 1β 활성이 연루된 상태의 예방 및 치료를 위한 NLRP3 조절제인 일반식 (I)의 신규 헤테로시클릭 화합물들을 개시한다. 보다 구체적으로, 본 발명의 구체예들은 림프종, 자가면역 질환, 이종면역 질환, 염증성 질환, 암 및 신경퇴행성 질환 또는 상태를 포함하는(그러나 이에 제한되지 않음) 다양한 병리학적 상태의 치료에서 치료제로서 유용하다.
[발명의 요약]
본 발명은 NLRP3에 의해 매개되는 질병 상태의 예방 및 치료뿐만 아니라 인터루킨 1β 활성이 연루된 질병 또는 상태의 치료를 위한 NLRP3 조절제인 일반식 (I)에 의해 정의된 바와 같은 헤테로시클릭 화합물을 개시한다. 본 발명의 화합물들은 NLRP3의 억제에 의해, 인간 또는 동물 신체의 치료에 유용하다. 본 발명의 화합물들은 따라서 NLRP3에 의해 매개되는 질병 상태의 예방 및 치료에 적합하다.
[발명의 구체예(들)]
본 발명의 일 구체예는 일반식 (I)로 표시되는 신규 헤테로시클릭 화합물, 이의 호변이성질체 형태, 이의 거울상이성질체, 이의 부분입체이성질체, 이의 입체이성질체, 이의 약학적으로 허용가능한 염 및 이들 또는 이들의 혼합물을 함유하는 약학적 조성물을 제공한다.
본 발명의 또 다른 구체예에서, 일반식 (I)의 화합물, 이의 호변이성질체 형태, 이의 거울상이성질체, 이의 부분입체이성질체, 이의 입체이성질체, 이의 약학적으로 허용가능한 염 또는 이들의 혼합물을 함유하는 약학적 조성물로서, 이러한 조성물을 제조하는 데 일반적으로 사용되는 적합한 담체, 용매, 희석제 및 기타 매질과 조합된 것을 제공한다.
추가 구체예에서, 치료적 유효량 및 무독성량의 일반식 (I)의 화합물 또는 이의 약학적으로 허용가능한 조성물을 포유동물에게 투여하는 것에 의한, NLRP3 조절제로서의 본 발명의 헤테로시클릭 화합물의 용도를 제공한다.
또 다른 추가 구체예에서, 본 발명의 식 (I)의 화합물은 하나 이상의 적합한 약학적 활성제와 조합하여 사용될 수 있다.
또 다른 구체예에서, 본 발명의 신규 화합물을 제조하는 방법을 제공한다.
본 발명의 추가 목적은 상기 방법에 관련된 신규 중간체를 제공하는 것이다.
본 발명의 추가 목적은 상기 방법에 관련된 중간체의 제조 방법을 제공하는 것이다.
따라서, 본 발명은 일반식 (I)의 화합물,
식 (I)
이의 호변이성질체 형태, 이의 입체이성질체, 이의 거울상이성질체, 이의 약학적으로 허용가능한 염, 및 이들을 함유하는 약학적 조성물에 관한 것으로, 여기에서,
R1은 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 시아노, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C2-C6)알케닐, (C1-C6)알콕시, (C3-C7)시클로알킬, NH2, NH(C1-C6)알킬, N(C3-C7)시클로알킬; N(C1-C6 알킬)2, 아릴, 헤테로아릴, 헤테로시클릴, 벤질, 티올, 메르캅토 알킬, SO2(C1-C6)알킬, (C1-C6)티오-알콕시, 아미드로부터 선택된 기를 나타내고;
m 및 n은 독립적으로 정수 0 내지 3으로부터 선택되고;
q 및 r은 독립적으로 정수 1 내지 4로부터 선택되고;
X는 N-R5; O, S, SO2이고;
R5는 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 시아노, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C2-C6)알케닐, (C2-C6)알키닐, (C1-C6)알콕시, (C3-C7)시클로알킬, (C1-C6)알킬SO2(C1-C6)알킬, (C1-C6)알킬N(C1-C6)알킬, (C1-C6)알킬N(C3-C7)시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴, 벤질, tert-부틸옥시카르보닐, 티올, 메르캅토알킬, SO2(C1-C6)알킬, SO2(C3-C7)시클로알킬, SO2-아릴, SO2-헤테로시클릴, (C1-C6)티오알킬, (C1-C6)티오알콕시, (C1-C6)알킬SO2NH2, -CONH2, -CO(C1-C6)알킬, -CO(C1-C6)할로알킬, -CO-아릴, -CO-헤테로아릴, -CO-헤테로시클릴, 4- 내지 7-원 헤테로시클릭 고리, 7- 내지 14-원 바이시클릭 헤테로시클릭 고리 시스템, 선택적으로 하나 이상의 헤테로원자를 갖는 가교 또는 스피로 고리 시스템으로부터 선택된 기를 나타내고;
R2는 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 시아노, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)알콕시, (C2-C6)알케닐, (C3-C7)시클로알킬, 벤질, 아릴, 헤테로아릴, 헤테로시클릴, 티올, 티오알킬, 티오-알콕시, SO2(C1-C6)알킬, SO(C1-C6)알킬, 선택적으로 하나 이상의 헤테로원자를 갖는 가교 또는 스피로 고리 시스템으로부터 선택된 기를 나타내고;
각각의 R3 및 R4는 각 경우에 수소, 할로겐, 할로알킬, 시아노, 니트로, 아미드, 설폰아미드, 아실, 히드록실, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C3-C6)시클로알킬, (C1-C6)알콕시, SO2(C1-C6)알킬, 티올, 메르캅토 알킬 벤질, 아릴, 헤테로아릴, 헤테로시클릴로부터 선택된 기를 나타내고; 대안적으로 R3 및 R4는 결합을 형성하고;
'B'는 하기 고리 시스템으로부터 선택되고,
여기에서 X, Y, Z는 각 경우에 독립적으로 C, N, S, SO2 및 O를 나타내며, 이는 선택적으로 치환될 수 있고;
각각의 R6, R7, R8, R9 , R10 및 R11는 각 경우에 독립적으로 수소, 할로겐, 시아노, 아미드, 설폰아미드, 아실, 히드록실, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C3-C6)시클로알킬, (C1-C6)알콕시, 벤질, 아릴, 헤테로아릴, 헤테로시클릴로부터 선택된 기로부터 선택되며; 대안적으로 각각의 R7 및 R8 , R8 및 R9, R9 및 R10 또는 R10 및 R11는 가능한 경우, N, O, 및 S(O)p로 구성된 군으로부터 선택된 0 내지 2개의 추가 헤테로원자를 함유하는 4 내지 7원 포화 또는 부분 포화 고리를 함께 형성할 수 있고; p = 1 내지 2이다.
임의의 상기 정의된 기가 치환되는 경우, 이들 상의 치환기는 상기 설명된 것들로부터 선택될 수 있거나, 수소, 히드록시, 시아노, 할로, 할로알킬, 할로알킬옥시, 알킬티오 (C1-C6)알킬, (C2-C6)알케닐, (C2-C6)알키닐, (C3-C7)시클로알킬, C1-C6 알콕시, 아릴, 헤테로시클릴, 헤테로아릴, -COR12, -CSR12, C(O)OR12, C(O)-R12, -C(O)-NR12R13, -C(S)-NR12R13, -SO2R12 기로부터 선택될 수 있으며, 여기에서 각각의 R12 및 R13은 독립적으로 수소, 선택적으로 치환된 (C1-C6)알킬, (C2-C6)알케닐, (C2-C6)알키닐, (C3-C7)시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴 기로부터 선택된 기로부터 선택된다;
바람직한 구체예에서, R1은 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 선택적으로 치환된 (C1-C6)알킬로부터 선택된 기를 나타낸다;
바람직한 구체예에서, R2는 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 선택적으로 치환된 (C1-C6)알킬로부터 선택된 기를 나타낸다;
바람직한 구체예에서, 각각의 R3 및 R4는 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 선택적으로 치환된 (C1-C6)알킬로부터 선택된 기를 나타낸다.
바람직한 구체예에서, 각각의 R6, R7, R8, R9 , R10 및 R11은 각 경우에 독립적으로 수소, 할로겐, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬로부터 선택된 기로부터 선택된다;
바람직한 구체예에서, 상기 설명된 기, 라디칼은 하기로부터 선택될 수 있다:
"알킬(Alkyl)", 뿐만 아니라 알콕시(alkoxy) 및 알카노일(alkanoyl)과 같은 접두사 "alk"를 갖는 다른 기는, 탄소 사슬이 달리 정의되지 않는 한, 당업자에 의해 잘 이해되는 바와 같이 산소 원자로 추가로 치환될 수 있고, 추가로 선형 또는 분지형 및 이들의 조합일 수 있는 탄소 사슬을 의미한다. 알킬 기의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, sec-부틸, tert. -부틸, 펜틸, 헥실 등을 포함하나, 이에 제한되지 않는다. 지정된 수의 탄소 원자가 허용되는 경우, 예를 들어 C3-10, 용어 알킬은 또한 시클로알킬 기, 및 시클로알킬 구조와 결합된 선형 또는 분지형 알킬 사슬의 조합을 포함한다. 탄소 원자의 수가 지정되지 않은 경우, C1-6이 의도된다. 치환된 알킬은 할로 {예: CI, F, Br, 및 I); 할로겐화 알킬 {예: CF3, 2-Br-에틸, CH2F, CH2CI, CH2CF3, 또는 CF2CF3); 히드록실; 아미노; 카르복실레이트; 카르복스아미도; 알킬아미노; 아릴아미노; 알콕시; 아릴옥시; 니트로; 아지도; 시아노; 티오; 설폰산; 설페이트; 포스폰산; 포스페이트; 및 포스포네이트 뿐만 아니라 '선택적으로 치환된'의 정의 하에 설명된 것들로 구성된 군으로부터 선택된 하나 이상의 모이어티로 치환된 알킬을 포함한다.
"알케닐(Alkenyl)"은 탄소 사슬이 달리 정의되지 않는 한, 적어도 하나의 탄소-탄소 이중 결합을 함유하고, 선형 또는 분지형 또는 이의 조합일 수 있는 탄소 사슬을 의미한다. 알케닐의 예는 비닐, 알릴, 이소프로페닐, 헥세닐, 펜테닐, 헵테닐, l -프로페닐,: 2-부테닐, 2-메틸 -2-부테닐 등을 포함하나, 이에 제한되지 않는다. 지정된 수의 탄소 원자가 허용되는 경우, 예를 들어 C5-10, 용어 알케닐은 또한 시클로알케닐 기 및 선형, 분지형 및 시클릭 구조의 조합을 포함한다. 탄소 원자의 수가 지정되지 않은 경우, C2-6이 의도된다.
"알키닐(Alkynyl)"은 적어도 하나의 탄소-탄소 삼중 결합을 함유하고, 선형 또는 분지형 또는 이의 조합일 수 있는 탄소 사슬을 의미한다. 알키닐의 예는 에티닐, 프로파르길, 3-메틸- 1 -펜티닐 등을 포함한다. 탄소 원자의 수가 지정되지 않는 경우, 의도된다.
단독으로 또는 다른 라디칼과 조합하여 사용되는 "티오알킬(thioalkyl)" 기는 식 -SR'(황 및 그의 산화된 형태)의 기에 부착된 상기 정의된 바와 같은 알킬 기를 나타내며, 여기에서 R'는 수소, 알킬 또는 알킬 기, 예를 들어, 티오메틸, 메틸티오메틸, 펜틸티오메틸 등을 나타내며, 이는 선택적으로 치환될 수 있다.
본원에서 사용된, "카보사이클(carbocycle)" 또는 "카보시클릭 잔기(carbocyclic residue)"는 임의의 안정한 모노시클릭 또는 바이시클릭 또는 트리시클릭 고리를 의미하는 것으로 의도되며, 이들 중 임의의 것은 포화, 부분 불포화 또는 방향족일 수 있다. 이러한 카보사이클의 예는, 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵틸, 아다만틸, 시클로옥틸, [3.3.0]비시클로옥탄, [4.3.0]비시클로노난, [4.4.0]비시클로데칸 (데칼린), [2.2.2]비시클로옥탄, 플루오레닐, 페닐, 나프틸, 인다닐, 아다만틸, 또는 테트라히드로나프틸 (테트랄린)을 포함하나, 이에 제한되지 않는다. 더 넓은 관점에서, 용어 카보사이클은, 적용 가능한 경우, 시클로알킬, 페닐 및 기타 포화, 부분 포화 또는 방향족 잔기를 나타내는 기를 포함하는 것으로 의도된다;
용어 "시클로알킬(cycloalkyl)" 및 "시클로알케닐(cycloalkenyl)"은 임의로 치환된, 포화 및 불포화 모노시클릭, 바이시클릭 또는 트리시클릭 탄소 기를 지칭한다. 적절한 경우, 시클로알킬 또는 시클로알케닐 기는 지정된 수의 탄소 원자를 가질 수 있으며, 예를 들어, C3-C6 시클로알킬 또는 시클로알케닐은 그의 범위 내에 3, 4, 5 또는 6개의 탄소 원자를 갖는 카보시클릭 기를 포함한다. 이러한 치환의 예는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로펜테닐, 시클로헥실, 시클로헥세닐, 시클로헥사디에닐 등으로 구성된 군으로부터 선택될 수 있다. 치환된 시클로알킬 또는 시클로알케닐은 할로 (예: CI, F, Br, 및 I); 할로겐화 알킬 (예: CF3, 2-Br-에틸, CH2F, CH2CI, CH2CF3, 또는 CF2CF3); 히드록실; 아미노; 카르복실레이트; 카르복스아미도; 알킬아미노; 아릴아미노; 알콕시; 아릴옥시; 니트로; 아지도; 시아노; 티오; 설폰산; 설페이트; 포스폰산; 포스페이트; 및 포스포네이트 뿐만 아니라 '선택적으로 치환된'의 정의 하에 설명된 것들로 구성된 군으로부터 선택된 하나 이상의 모이어티로의 치환을 포함한다.
"알콕시(alkoxy)"는 지정된 탄소 원자의 수의 직쇄 또는 분지쇄 알콕시드를 지칭한다.
"아릴(Aryl)"은 탄소 고리 원자를 함유하는 모노- 또는 폴리시클릭 방향족 고리 시스템을 의미한다. 바람직한 아릴은 모노시클릭 또는 바이시클릭 6-10원 방향족 고리 시스템이다. 페닐 및 나프틸이 바람직한 아릴이다.
"헤테로시클릴(Heterocyclyl)"은 질소, 황 및 산소로부터 선택되는 하나 이상의 헤테로원자를 함유하고, 추가로 선택적으로 황의 산화된 형태, 즉 SO 및 SO2를 포함하는, 포화, 부분 포화 또는 불포화 방향족 또는 비-방향족 모노, 비 또는 트리시클릭 라디칼을 의미한다. 헤테로시클릴 시스템은 라디칼의 임의의 수의 탄소 원자 또는 헤테로원자를 통해 또 다른 모이어티에 부착될 수 있으며, 포화 및 불포화 둘 모두일 수 있다. 헤테로사이클의 예는 테트라히드로퓨란 (THF), 디히드로퓨란, 1 ,4-디옥산, 모르폴린, 1,4-디티안, 피페라진, 피페리딘, 1 ,3-디옥솔란, 이미다졸린, 이미다졸리딘, 피롤리딘, 피롤린, 테트라히드로피란, 테트라히드로-2H-티오피란, 디히드로피란, 옥사티올란, 디티올란, 1 ,3-디옥산, 1 ,3-디티안, 옥사티안, 티오모르폴린 등을 포함한다. 용어 "헤테로시클로알킬(heterocycloalkyl)"은 상기 정의된 바와 같은 알킬 기에 연결된 상기 정의된 바와 같은 헤테로시클릭 기를 지칭한다;
"헤테로아릴(Heteroaryl)"은 O, S 및 N으로부터 선택된 적어도 하나의 고리 헤테로원자를 함유하는 방향족 또는 부분 방향족 헤테로사이클을 의미한다. 헤테로아릴은 따라서 방향족이 아닌 아릴, 시클로알킬 및 헤테로사이클과 같은 다른 종류의 고리에 융합된 헤테로아릴을 포함한다. 헤테로아릴 기의 예는 피롤릴, 이속사졸릴, 이소티아졸릴, 피라졸릴, 피리딜, 옥사졸릴, 옥사디아졸릴, 티아디아졸릴, 티아졸릴, 이미다졸릴, 트리아졸릴, 테트라졸릴, 퓨릴, 트리아지닐, 티에닐, 피리미딜, 벤즈이속사졸릴, 벤즈옥사졸릴, 벤즈티아졸릴, 벤조티아디아졸릴, 디히드로벤조퓨라닐, 인돌리닐, 피리다지닐, 인다졸릴, 이소인돌릴, 디히드로벤조티에닐, 인돌리닐, 피리다지닐, 인다졸릴, 이소인돌릴, 디히드로벤조티에닐, 인돌리지닐, 신놀리닐, 프탈라지닐, 퀴나졸리닐, 나프티리디닐, 카르바졸릴, 벤조디옥솔릴, 퀴녹살리닐, 퓨리닐, 퓨라자닐, 이소벤질퓨라닐, 벤즈이미다졸릴, 벤조퓨라닐, 벤조티에닐, 퀴놀릴, 인돌릴, 이소퀴놀릴, 디벤조퓨라닐 등을 포함한다. 헤테로시클릴 및 헤테로아릴 기의 경우, 3 내지 15개의 탄소 원자를 함유하는 고리 및 고리 시스템이 포함되어, 1 내지 3개의 고리를 형성한다.
용어 "할로알킬(haloalkyl)"은 적어도 하나의 수소가 할로겐 원자로 대체된 알킬 구조를 의미한다. 2개 이상의 수소 원자가 할로겐 원자로 대체된 특정 구체예에서, 할로겐 원자는 모두 서로 동일하다.
"할로알콕시(haloalkoxy)" 기는 산소 원자에 직접 부착된 상기 정의된 바와 같은 적합한 할로알킬로부터 선택되며, 보다 바람직하게는 플루오로메톡시, 클로로메톡시, 플루오로에톡시, 클로로에톡시 등으로부터 선택되는 기이다;
2개 이상의 수소 원자가 할로겐 원자로 대체된 특정 다른 구체예에서, 할로겐 원자는 모두 서로 동일하지 않다.
"아릴옥시알킬(Aryloxyalkyl)"은 본원에서 정의된 바와 같은 아릴옥시 기로 치환된 알킬 라디칼을 의미한다.
"아릴옥시아릴(Aryloxyaryl)"은 본원에서 정의된 바와 같은 아릴옥시 기로 치환된 아릴 라디칼을 의미한다.
"아릴옥시헤테로아릴(Aryloxyheteroaryl)"은 본원에서 정의된 바와 같은 아릴옥시 기로 치환된 헤테로아릴 라디칼을 의미한다.
"할로/할로겐"은 플루오린, 클로린, 브로민, 아이오딘을 지칭한다. 클로린 및 플루오린이 일반적으로 바람직하다.
적합한 기 및 기 상의 치환기는 명세서의 어느 곳에서나 설명된 것들로부터 선택될 수 있다.
본원에서 사용된 용어 "치환된"은 지정된 원자 상의 임의의 하나 이상의 수소가 지시된 기로부터의 선택으로 대체되고, 단 지정된 원자의 정상 원자가를 초과하지 않으며, 치환은 안정한 화합물을 생성함을 의미한다. 본원에서 사용된 용어 "치환된"은 지정된 원자 상의 임의의 하나 이상의 수소가 지시된 기로부터의 선택으로 대체되고, 단 지정된 원자의 정상 원자가를 초과하지 않으며, 치환은 안정한 화합물을 생성함을 의미한다.
"약학적으로 허용가능한 염"은 모 화합물이 그의 산 또는 염기 염을 제조함으로써 변형된 개시된 화합물의 유도체를 지칭한다. 약학적으로 허용가능한 염의 예는 염기성 잔기의 무기산염 또는 유기산염을 포함하나, 이에 제한되지 않는다. 이러한 통상적인 무독성 염은 소듐, 포타슘, 1,2-에탄디설폰산, 2-아세트옥시벤조산, 2-히드록시에탄설폰산, 아세트산, 아스코르브산, 벤젠술폰산, 벤조산, 중탄산, 탄산, 시트르산, 에데트산, 에탄 디설폰산, 에탄 설폰산, 퓨마르산, 글루코헵톤산, 글루콘산, 글루탐산, 글리콜산, 글리콜리아르사닐릭산, 헥실레조르신산, 히드라바믹산, 히드로브로미, 히드로클로릭산, 히드로아이오다이드, 히드록시말레산, 히드록시나프토에산, 이세티온산, 젖산, 락토바이온산, -라우릴 설폰산, 말레산, 말산, 만델산, 메탄설폰산, 나프실산, 질산, 옥살산, 파모익산, 판토텐산, 페닐아세트산, 인산, 폴리갈락투론산, 프로피온산, 살리실릭산, 스테아르산, 서브아세트산, 숙신산, 설팜산, 설파닐산, 황산, 타닌산, 타르타르산, 및 톨루엔설폰산으로부터 선택된 무기산 및 유기산으로부터 유도된 것을 포함하나, 이에 제한되지 않는다.
용어 '선택적' 또는 '선택적으로'는 이후에 설명된 사건 또는 상황이 발생할 수도 있고 발생하지 않을 수도 있음을 의미하며, 설명은 해당 사건 또는 상황이 발생한 경우와 발생하지 않은 경우를 포함한다. 예를 들어, 선택적으로 치환된 알킬은 '알킬' 또는 '치환된 알킬'을 의미한다. 또한 선택적으로 치환된 기는 비치환된 기를 포함한다.
명세서에서 달리 언급되지 않는 한, 본원에 도시된 구조는 또한 하나 이상의 동위원소 풍부 원자의 존재에서만 차이가 있는 화합물을 포함하는 것을 의미한다.
특히 유용한 화합물은 하기로부터 선택될 수 있으나, 이에 제한되지 않는다:
(R,E)-2-(1-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드;
(S,E)-2-(1-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-프로필피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-(시클로프로필메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)-피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-아세틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐-1-설폰아미드;
(E)-2-(1-벤질피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드;
tert-부틸 (R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)피롤리딘-1-카르복실레이트;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-메톡시에틸)피롤리딘-2-일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(이소프로필설포닐)피롤리딘-2-일)에텐설폰아미드;
(R,E)-2-(1-((3-플루오로페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(피라진-2-카르보닐)피롤리딘-2-일)에텐설폰아미드;
(R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복스아미드;
(R,E)-2-(1-(시클로프로판카르보닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2,2,2-트리플루오로아세틸)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-(메틸티오)에틸)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2,2,2-트리플루오로에틸)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소부틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-(에틸설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소프로필피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(3-(메틸설포닐)프로필)피롤리딘-2-일)에텐설폰아미드;
(R,E)-2-(1-벤조일피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(R,E)-N-((2-(1-벤조일피롤리딘-2-일)비닐)설포닐)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)벤즈아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티오펜-3-카르보닐)피롤리딘-2-일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 메탄 설포네이트;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 말리에이트;
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-3-(피롤리딘-2-일)프로프-1-엔-1-설폰아미드;
(R,E)-2-(1-(시클로헥실설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-(시클로헥실메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-시클로헥실피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(1-메틸피페리딘-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소프로필피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(옥세탄-3-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-티오피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티아졸-2-일메틸)피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-4-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피페리딘-4-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피페리딘-4-일)에텐설폰아미드;
(E)-2-(1-아세틸피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드;
tert-부틸 (E)-4-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-피페리딘-1-카르복실레이트;
(E)-2-(1-에틸피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-에틸피롤리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐설폰아미드;
(R,E)-1,1-디에틸-3-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)피롤리딘-1-이움브로마이드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-3-일)에텐-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-2-(1-아세틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-1,1-디에틸-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)-2-메틸피롤리딘-1-이움 브로마이드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(메틸설포닐)-피롤리딘-2-일)에텐-1-설폰아미드;:
(R,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-에틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-(시클로프로필메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐설폰아미드;
(S,E)-tert-부틸2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복실레이트;
(S,E)-2-(1-(시클로프로필메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(피리딘-3-일설포닐)-피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-에틸피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-(메틸설포닐)피롤리딘-2-일)에텐-설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐설폰아미드;
(S,E)-2-(1-아세틸피롤리딘-2-일)-N-((2,6-디이소프로필페닐)카르바모일)에텐설폰아미드;
(S,E)-2-(1-아세틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-카르보닐)피롤리딘-2-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(테트라히드로-2H-피란-4-일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-니코티노일피롤리딘-2-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(테트라히드로퓨란-2-일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티오펜-2-일메틸)-피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (S,E)-2-(2-(N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-피롤리딘-1-카르복실레이트;
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소부틸-2-메틸-피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-프로필피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티아졸-2-일)피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-3-일)에텐-설폰아미드;
(E)-2-(1-에틸피페리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드;
(E)-tert-부틸 3-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-피페리딘-1-카르복실레이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피페리딘-3-일)에텐설폰아미드;
(E)-2-(1-아세틸피페리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드;
tert-부틸 (E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-아제티딘-1-카르복실레이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸아제티딘-2-일)에텐-1-설폰아미드;
(E)-2-(아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(1-((5-클로로티오펜-2-일)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-(벤질설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-((4-메톡시페닐)설포닐) 피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-((4-플루오로페닐)설포닐) 피롤리딘-2-일)에텐설폰아미드;
(S,E)-2-(1-((2-시아노페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-(시클로헥실설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-(4-플루오로벤질)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-((4-시아노페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(4-시아노벤질)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피페리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피롤리딘-2-일)에텐-1-설폰아미드;
((E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-3-(피페리딘-2-일)프로프-1-엔-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(인돌린-2-일)에텐-1-설폰아미드;
tert-부틸(E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)인돌린-1-카르복실레이트;
((S,E)-2-(1-(시클로프로필메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(시클로프로필설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (S,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
tert-부틸 (R,E)-2-(2-(N-((2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(R,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1,2-디메틸피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(1-에틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
비스 소듐 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
소듐 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
tert-부틸 (S,E)-2-(2-(N-((2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1,2-디메틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(옥세탄-3-일)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (S,E)-2-(2-(N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)에텐-1-설폰아미드;
(E)-2-(1-아세틸아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)에틸)(메틸)카바메이트;
(S,E)-2-(1-알릴피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(1H-벤조[d]이미다졸-6-카르보닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(시클로프로필설포닐)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(4-메톡시벤질)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)헥사히드로시클로펜타[c]피롤-2(1H)-카르복실레이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-((2R)-1-(옥타히드로시클로-펜타[c]피롤-5-일)피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(E)-2-(1-(시클로프로필설포닐)아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-(티아졸-2-일)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-일)에틸)(메틸)카바메이트;
포타슘 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
tert-부틸 (E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)아제티딘-1-일)에틸)(메틸)카바메이트;
(S,E)-2-(1-(시클로헥실메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
소듐 (R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-(테트라히드로-2H-티오피란-4-일)피롤리딘-2-일)비닐)설포닐)아미드;
소듐 (R,E)-((2-(1-시클로헥실피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
소듐 (S,E)-((2,6-디이소프로필페닐)카르바모일)((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)아미드;
소듐 (R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-메틸피롤리딘-2-일)비닐)설포닐)아미드;
포타슘 (R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-메틸피롤리딘-2-일)비닐)설포닐)아미드;
소듐 (S,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
소듐 (S,E)-((2-(1-에틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-히드록시에틸)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-카르복실레이트;
(E)-2-(1,2-디메틸아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (S,E)-2-에틸-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복실레이트;
tert-부틸 (S,E)-2-(2-(N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(S,E)-2-(2-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(S,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (R,E)-2-(2-(N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(R,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (R,E)-2-(3-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)알릴)-2-메틸피롤리딘-1-카르복실레이트;
tert-부틸 (R,E)-(2-(2-(3-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)알릴)-2-메틸피롤리딘-1-일)에틸)(메틸)카바메이트;
(R,E)-3-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)프로프-1-엔-1-설폰아미드;
tert-부틸 (S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)프로필)(메틸)카바메이트;
tert-부틸 (E)-(3-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)프로필)(메틸)카바메이트;
tert-부틸 (E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)에틸)(메틸)카바메이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(2-(메틸티오)에틸)아제티딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(옥세탄-3-일)아제티딘-2-일)에텐-1-설폰아미드;
tert-부틸 (S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)메틸)-2-메틸피롤리딘-1-카르복실레이트;
tert-부틸 (S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)메틸)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-설파모일에틸)피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(2-에틸-1-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-(부트-2-인-1-일)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
또는 상기 화합물들 중 임의의 것의 약학적으로 허용가능한 염.
다음은 본 발명의 화합물의 제조의 설명에서 사용된 약어의 목록이다:
μg: 마이크로그램
1H NMR : 양성자 핵자기 공명(Proton nuclear magnetic resonance)
bs: 넓은 일중선(broad singlet)
CDC13: 중수소로 치환된 클로로포름(Deuterated chloroform)
CHC13: 클로로포름
d: 이중선(doublet)
DAMP: 손상-연관 분자 패턴(damage-associated molecular pattern);
DCM: 디클로로메탄(Dichloromethane)
dd: 이중선의 이중선(doublet of doublet)
DMAC: N,N-(디메틸아세트아미드)
DMAP: 4-(디메틸아미노)피리딘
DMF: N,N-디메틸 포름아미드
DMSO: 디메틸 설폭사이드
dt: 삼중선의 이중선(doublet of triplet)
EDTA: 에틸렌디아민테트라아세트산(Ethylenediaminetertraacetic acid)
EtOAc: 에틸 아세테이트
EtOH: 에탄올
HCl(g): 염화수소 (gas)
IL1β: 인터루킨 1 베타
K2CO3: 탄산칼륨
LPS: 지질다당류(Lipopolysaccharide)
m: 다중선(multiplet)
MeOH: 메탄올
mmol: 밀리몰(millimoles)
MS: 질량 스펙트럼(Mass spectrum)
N2: 질소
Na2CO3: 탄산나트륨
ng: 나노그램
NIS: N-아이오도석신이미드
NLRP3: NOD-유사 수용체 패밀리, 피린 도메인-함유 단백질 3(NOD-like receptor family, pyrin domain-containing protein 3)
PAMP: 병원체-연관 분자 패턴(pathogen-associated molecular pattern);
PMA: 포볼12-미리스테이트 13-아세테이트(Phorbol 12-myristate 13-acetate)
POCI3: 포스포릴클로라이드(Phosphorylchloride)
RM: 반응 혼합물(reaction mixture)
R.T; r.t: 실온(room temperature)
s: 일중선(singlet)
t: 삼중선(Triplet)
td: 이중선의 삼중선(triplet of doublet)
THF: 테트라히드로퓨란(Tetrahydrofuran)
TLC: 박층크로마토그래피(Thin layer chromatography)
TLR: Toll-유사 수용체(Toll-like receptor).
TNFα: 종양 괴사 인자 알파(Tumor necrosis factor alpha)
일반적 제조 방법
본 발명의 신규 화합물들은 유기 합성 분야의 당업자에게 공지된 통상적인 기술, 또는 당해 분야의 당업자에 의해 인식되는 그에 대한 변형과 함께, 하기에 설명된 반응 및 기술을 사용하여 제조될 수 있다.
반응은 사용된 시약 및 물질에 적절하고 영향을 받는 변환에 적합한 용매에서 수행될 수 있다. 바람직한 방법은 아래에 설명된 방법을 포함하나, 이에 제한되지 않으며, 여기에서 모든 기호는 아래에서 달리 정의되지 않는 한 앞서 정의된 바와 같다.
일반식 (I)의 화합물은 당업자의 범위 내에 있는 적합한 수정/변형과 함께 하기 반응식에 설명된 바와 같이 제조될 수 있다.
반응식 1
반응식 2
반응식 3
여기에서 각각의 A, B, R1, R2, R3 , 및 R4는 앞서 정의된 바와 같다. 화합물 (2)는 시판되는 메탄 설폰아미드 (1)로부터 Boc 무수물과 같은 시약을 사용하여 당업자에게 친숙한 다양한 방법에 의해 제조될 수 있다. 화합물 (2)는 적합한 조건 및 적절한 용매 하에서 디페닐포스핀산 클로라이드로 처리하여 화합물 3을 제공하였다(참조: Synthesis 2003, 15, 2321-24). 화합물 3은 소듐 하이드라이드와 같은 염기 및 적절한 용매의 존재에서 적합한 조건 하에 알데히드 또는 케톤 유도체 (4)로 처리하여 화합물 (5)를 제공하였고, 이는 적합한 조건 하에 탈보호하여 화합물 (6)을 제공할 수 있다. 화합물 (3)은 소듐 하이드라이드와 같은 염기 및 적절한 용매의 존재에서 적합한 조건 하에 이소시아나토 유도체 (7)로 처리하여 식 (I)의 화합물을 제공한다 (반응식 1). 대안적으로, 식 (I)의 화합물은 또한 반응식 2 및 반응식 3에 도시된 바와 같이 제조될 수 있다.
상기 설명된 바와 같은 방법 단계를 수행하는 데 필요한 특정 반응 조건, 용매 및 기타 파라미터는 당업자의 능력 범위 내에 있다.
본 발명은 본 발명을 수행하는 바람직한 방법을 설명하는 하기 비제한적인 실시예에 의해 추가로 설명된다. 이들은 어떤 식으로든 본 발명의 범위를 제한하지 않고 제공된다.
실시예에서 주어진 1H NMR 스펙트럼 데이터(아래 참조)는 40 MHz 분광계(Bruker AVANCE-400)를 사용하여 기록되고, δ 스케일로 보고된다. 달리 언급되지 않는 한 NMR에 사용된 용매는 내부 표준으로 TMS를 사용하는 CDCl3이다.
본 발명의 특징에 따르면, 식 (5)의 중간체의 일반 구조가 제공되며,
여기에서 모든 기호는 상기에서 정의된 바와 같다.
또 다른 구체예에서, 식 (6)의 중간체의 일반 구조가 제공되며,
여기에서 모든 기호는 상기에서 정의된 바와 같다.
또 다른 구체예에서, 식 (15)의 중간체의 일반 구조가 제공되며,
여기에서 모든 기호는 상기에서 정의된 바와 같다.
또 다른 구체예에서, 식 (16)의 중간체의 일반 구조가 제공되며,
여기에서 모든 기호는 상기에서 정의된 바와 같다.
또 다른 구체예에서, 명세서에 개시된 반응식 1 및 3에 따라 식 (5), (6), 15) 및 16)의 중간체의 제조 방법이 제공된다.
중간체-1a:
tert-부틸 (R,E)-2-(2-(N-(tert-부톡시카르보닐)-설파모일)-비닐)피롤리딘-1-카르복실레이트의 제조
500 mL, 3구, 둥근 바닥 플라스크에 자기 교반기, N2 풍선, 보온병 주머니, 드라이 아이스 배스가 장착되어 있다. tert-부틸 ((디페닐포스포릴)메틸)설포닐카바메이트 (3) (10 g, 25.3 mmol)를 질소 분위기 하에 DMF (100 mL)에 용해시켰다. 이를 -20°C로 냉각하고, NaH (2.023 g, 50.6 mmol)를 첨가하였다. 이를 25°C로 서서히 가온하고, 30분 동안 교반하였다. 다시 -20°C로 냉각하고, DMF (50 mL) 중 (R)-tert-부틸 2-포르밀피롤리딘-1-카르복실레이트 (Org. Lett. 2008, 10, 4, 3045-3048) (6.05 g, 30.3 mmol)의 용액을 1시간 동안 - 20°C 온도에서 적가하였다. 첨가 후 반응 혼합물을 실온으로 가온하고, 17시간 동안 추가로 교반하였다. 반응 혼합물을 0°C로 냉각하고, 포화 시트르산 용액 (30 mL) 및 물 (200 mL)로 산성화하고, 고체를 침전시키고, 이를 여과하고, 세척하고, 건조하여, (R,E)-tert-부틸 2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)피롤리딘-1-카르복실레이트 (4.6 g, 12.22 mmol, 48 % 수율)를 수득하였다.
1H NMR (400 MHz, DMSO-d 6 ): δ = 11.33 (s, 1H), 6.78 - 6.67 (m, 1H), 6.52 (d, J = 14.2 Hz, 1H), 4.50 - 4.42 (m, 1H), 3.33 - 3.27 (m, 2H), 2.1 (br s, 1H), 1.79 - 1.71 (m, 3H), 1.44 - 1.35 (m, 18H); MS (ESI): m/z (%) = 375.30 (100%) (M-H)-.
중간체-1b:
tert-부틸 (S,E)-2-(2-(N-(tert-부톡시카르보닐)-설파모일)-비닐)피롤리딘-1-카르복실레이트의 제조
중간체-1b는 또한 (S)-tert-부틸 2-포르밀피롤리딘-1-카르복실레이트를 사용하여 중간체-1a의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-2a:
(R,E)-tert-부틸 2-(2-설파모일비닐)피롤리딘-1-카르복실레이트의 제조
화합물 [중간체 1a] (18 g)을 DMSO (180 mL)에 용해시키고 85oC로 가열하였다(출발 물질의 소멸은 TLC에 의해 모니터링됨). 반응물을 냉각시키고, 물 (900 mL)에 붓고, EtOAc (3 x 300 mL)로 추출하였다. 용매를 진공에서 농축시키고, 실리카겔 컬럼 크로마토그래피 (50% EtOAc:n-헥산)에 의해 정제하여 생성물 (R,E)-tert-부틸 2-(2-설파모일비닐)피롤리딘-1-카르복실레이트 (14.3 g, 53.7 mmol, 67% 수율)를 얻었다.
1H NMR (400 MHz, DMSO-d 6 ): δ = 6.99 (s, 2H), 6.40 - 6.38 (m, 1H), 6.34 - 6.30 (m, 1H), 4.40 - 4.32 (m, 2H), 3.28 - 3.25 (m, 1H), 2.21 - 1.99 (m, 1H), 1.81 - 1.67 (m, 3H), 1.38 (m, 9H); MS (ESI): m/z (%) = 299.09 (50%) (M+Na)+, 275.09 (100%) (M-1).
중간체-2b:
(S,E)-tert-부틸 2-(2-설파모일비닐)피롤리딘-1-카르복실레이트의 제조
중간체-2b는 또한 중간체 1b를 사용하여 중간체-2a의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-2c:
tert-부틸 (R,Z)-2-(2-설파모일비닐)피롤리딘-1-카르복실레이트의 제조
중간체-2c는 또한 중간체-2a의 합성에 대해 설명된 절차에 따라 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.06 (s, 2H), 6.22 (d, J = 12 Hz, 1H), (dd, J = 12 Hz, J = 11.2 Hz, 1H), 5.24 - 4.92 (m, 1H), 3.41 - 3.23 (m, 1H), 2.31 - 2.03 (m, 2H), 1.99 - 1.71 (m, 1H), 1.68 - 1.62 (m, 1H), 1.39 (m, 9H); MS (ESI): m/z (%) = 299.09 (40%) (M+Na)+.
중간체-2d:
tert-부틸 (S,Z)-2-(2-설파모일비닐)피롤리딘-1-카르복실레이트의 제조
중간체-2d는 또한 중간체-2b의 합성에 대해 설명된 절차에 따라 얻었다.
중간체-3a (실시예 10):
tert-부틸 (R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)피롤리딘-1-카르복실레이트의 제조
0°C에서 DMF (220 mL) 중 설폰아미드 [중간체 2a] (22.0 gm, 80 mmol)의 용액에 NaH (미네랄 오일 중 60% 분산액) (3.82 gm, 96 mmol)를 첨가하였다. 반응물을 실온으로 가온되도록 하고, 30분 동안 교반하였다. 4-이소시아나토-1,2,3,5,6,7-헥사히드로-s-인다센 (19.03 gm, 96 mmol)을 0°C에서 조금씩 첨가하고 반응물을 실온으로 가온하고, 밤새 교반하였다. 반응물을 50% 수성 시트르산을 사용하여 pH=2.0까지 산성화하고, 물 (1500 mL)로 희석하고, 침전물을 여과하고 건조하여 생성물(38 g, 80 mmol, 100% 수율)을 얻었다.
1H NMR (400 MHz, DMSO-d6): δ = 10.42 (s, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.71 - 6.68 (m, 1H), 6.59 (d, J = 14.8 Hz, 1H), 4.45 - 4.38 (m, 1H), 3.29 - 3.27 (m, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 2.30 - 1.93 (m, 5H), 1.78 - 1.71 (m, 3H), 1.39 - 1.33 (m, 9H); MS (ESI): m/z (%) = 498.18 (40%) (M+Na)+, 474.18 (100%) (M-1).
중간체-3b (실시예 61):
tert-부틸 (S,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)피롤리딘-1-카르복실레이트의 제조
중간체-3b는 또한 중간체-2b의 합성에 대해 설명된 절차에 따라 제조하였다.
1H NMR (400 MHz, DMSO): δ = 10.42 (bs, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.71-6.67 (m, 1H), 6.61-6.57 (m, 1H), 4.45-4.38 (m, 1H), 3.29-3.25 (m, 2H), 2.81 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.09-1.93 (m, 5H), 1.78-1.71 (m, 3H), 1.33 (s, 9H); MS (ESI): m/z (%) = 498.18 (80%) (M+Na)+.
중간체-4a: tert-부틸 (R)-2-포르밀-2-메틸피롤리딘-1-카르복실레이트의 제조
1-(tert-부틸) 2-메틸 (R)-2-메틸피롤리딘-1,2-디카르복실레이트 (Singh et. al., RSC Adv., 2013, 3, 19533-19544) (98 g, 403 mmol)의 용액에 건조 DCM (2000 mL) 중에서 용액을 얻었다. DIBAL-H (톨루엔 중 806 mL의 1.5M, 537 mmol)를 -78oC에서 적가하였다. 반응 혼합물을 78oC에서 2시간 동안 교반한 후, 메탄올 (100 mL)로 -78oC 온도에서 중지시켰다. 반응 혼합물을 50% 시트르산 용액으로 pH=4.0까지 산성화하였다. 물 (1000 mL) 및 DCM (1000 mL)을 첨가하였다. 수성층을 DCM (2X1500 mL)으로 추출하였다. 합한 유기층을 물 (1500 mL), 염수 (1000 mL)로 세척하고, Na2SO4로 건조시켰다. 용매를 제거하여 생성물(83 g, 389 mmol, 97 % 수율)을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 9.28 (m, 1H), 3.64 - 3.41 (m, 2H), 1.97 - 1.85 (m, 2H), 1.70 -1.50 (m, 2H), 1.38 - 1.28 (m, 12H), rotamers; MS (ESI): m/z (%) = 214.3 (100%) (M+H)+.
중간체-4b: tert-부틸 (S)-2-포르밀-2-메틸피롤리딘-1-카르복실레이트의 제조
중간체-4b는 또한 1-(tert-부틸) 2-메틸 (S)-2-메틸피롤리딘-1,2-디카르복실레이트를 사용하여 중간체-4a의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-5a:
tert-부틸 (R,E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트의 제조
0oC에서 DMF (1530 mL) 중 tert-부틸 (((디페닐포스포릴)메틸)설포닐)카바메이트 (153.0 gm, 387 mmol)의 용액에 NaH(미네랄 오일 중 60 % 분산액) (34 gm, 851 mmol)를 첨가하였다. 반응물을 실온으로 가온되도록 하고, 30분 동안 교반하였다. DMF (830mL) 중 알데히드 (tert-부틸 (R)-2-포르밀-2-메틸피롤리딘-1-카르복실레이트) (83 gm, 387 mmol)를 -20oC에서 적가하고, 반응물을 실온으로 가온하고, 밤새 교반하였다. 반응물을 50% 수성 시트르산 (~500 mL)을 사용하여 pH=2.0까지 산성화하고, 물 (3000 mL)로 희석하고, EtOAc (2000 mL x 2)로 추출하였다. 합한 유기층을 물 (2000 mL x 3), 염수 (1000 mL)로 세척하고, Na2SO4로 건조시키고, 농축 및 건조하여 조(crude) 생성물을 얻었다. 잔여물을 25% EtOAC: n-헥산을 사용하여 실리카겔 컬럼 크로마토그래피에 의해 정제하여, 표제 화합물(121 g, 310 mmol, 80% 수율)을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 11.35 (s, 1H), 6.78 (d, J = 15.2 Hz, 1H), 6.44 (d, J = 15.6 Hz, 1H), 3.42 - 3.36 (m, 2H), 1.99 - 1.92 (m, 1H), 1.88 - 1.59 (m, 3H), 1.49 - 1.36 (m, 21H); MS (ESI): m/z (%) = 413.15 (90%) (M+Na), 389.15 (100%) (M-1).
중간체-5b: tert-부틸 (S,E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트의 제조
중간체-5b는 또한 tert-부틸 (S)-2-포르밀-2-메틸피롤리딘-1-카르복실레이트를 사용하여 중간체-5a의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-6a: tert-부틸 (R,E)-2-메틸-2-(2-설파모일비닐)피롤리딘-1-카르복실레이트의 제조
중간체 5a (121 g)를 DMSO (1200 mL)에 용해시키고, 85oC로 가열하였다(출발 물질의 소멸은 TLC에 의해 모니터링됨). 반응물을 냉각시키고, 물 (3000 mL)에 붓고, EtOAc (2000 mL x 4)로 추출하고, Na2SO4로 건조하였다. 용매를 진공에서 농축하고, 실리카겔 컬럼 크로마토그래피 (50% EtOAc:n-헥산)에 의해 정제하여, 생성물(61.4 g, 211 mmol, 68.2 % 수율)을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 6.98 (s, 2H), 6.61 - 6.49 (m, 1H), 6.25 (d, J = 15.2 Hz, 1H), 3.43 - 3.35 (m, 2H), 1.99 - 1.66 (m, 4H), 1.47 - 1.43 (m, 3H), 1.40 - 1.37 (m, 9H); MS (ESI): m/z (%) = 289.13 (100%) (M-1).
중간체-6b:
tert-부틸 (S,E)-2-메틸-2-(2-설파모일비닐)피롤리딘-1-카르복실레이트의 제조
중간체-6b는 또한 중간체-5b를 사용하여 중간체-6a의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-7a (실시예 52): tert-부틸 (R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트의 제조
0oC에서 DMF (610 mL) 중 tert-부틸 (R,E)-2-메틸-2-(2-설파모일비닐)피롤리딘-1-카르복실레이트 (중간체 6a) (61.0 gm, 210 mmol)의 용액에 NaH (미네랄 오일 중 60% 분산액) (10.08 gm, 252 mmol)를 첨가하였다. 반응물을 실온으로 가온되게 하고, 30분 동안 교반하였다. 4-이소시아나토-1,2,3,5,6,7-헥사히드로-s-인다센 (50.2 gm, 252 mmol)을 0oC에서 조금씩 첨가하고, 반응물을 실온으로 가온하고, 밤새 교반하였다. 반응물을 50% 수성 시트르산을 사용하여 0oC에서 pH=2.0까지 산성화하고, 차가운 물 (3000 mL)로 희석하고, 침전물을 Buchner 깔때기를 통해 여과하고 건조하여 생성물(100 g, 204 mmol, 97 % 수율)을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.41 (s, 1H), 8.06 (s, 1H), 6.96 (s, 1H), 6.87 - 6.77 (m, 1H), 6.55 (d, J = 15.2 Hz), 3.43 - 3.37 (m, 2H), 2.81 (t, J = 6.8 Hz, 4H), 2.67 (t, J = 6.8 Hz, 4H), 2.00 - 1.93 (m, 5H), 1.86 - 1.65 (m, 3H), 1.41 - 1.43 (m, 3H), 1.40 - 1.38 (s, 9H); MS (ESI): m/z (%) = 488.16 (100%) (M-1).
중간체-7b (실시예 111): tert-부틸 (S,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트의 제조
중간체-7b (실시예 111)은 또한 중간체-6b를 사용하여 중간체-7a의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-8: (디페닐포스포릴)메탄설폰아미드의 제조
tert-부틸(((디페닐포스포릴)메틸)설포닐)카바메이트 (Synthesis 2003, 15, 2321-24) (10.0 g, 25.3 mmol)를 N2 분위기 하에 DCM (100 mL) 중에 용해시켰다. 이를 0°C 온도까지 냉각시키고, TFA (19.48 mL, 253 mmol)를 적가한 후, 아이스 배스를 제거하고, RM을 4시간 동안 추가로 교반하였다. TLC로 출발 물질이 관찰되지 않음을 확인하였다. R.M을 감압하에 농축하고, 물 (50 mL)을 첨가하고 고체를 침전시키고, 이를 여과하고 물 (25 mLX2)로 세척하고, P2O5로 건조하여 (디페닐포스포릴)메탄설폰아미드 (7.3 g, 24.72 mmol, 98 % 수율)를 수득하였다. 1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.86 - 7.81 (m, 4H), 7.61 - 7.51 (m, 6H), 6.84 (s, 2H), 4.63 (d, J = 9.2 Hz, 2H); MS (ESI): m/z (%) = 296.05 (100%) (M+H)+.
중간체-9: 1-(디페닐포스포릴)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)메탄설폰아미드의 제조
(디페닐포스포릴)메탄설폰아미드 [중간체 8] (6.0 g, 20.32 mmol)를 N2 분위기 하에 DMF (60 mL)에 녹였다. 이를 0°C 온도로 냉각시키고, NaH (1.170 g, 24.38 mmol)를 첨가하고, RM을 30분 동안 RT에서 교반한 후, DMF (15 mL) 중 4-이소시아나토-1,2,3,5,6,7-헥사히드로-s-인다센 (4.86 g, 24.38 mmol)의 용액을 첨가하고, RM을 17시간 동안 RT에서 추가로 교반하였다. TLC로 출발 물질이 관찰되지 않음을 확인하였다. 반응 혼합물을 아이스 냉수 (180 mL)에 붓고, 포화 시트르산으로 산성화하고, 교반하고, 여과하여 조 생성물을 얻었다. 이를 에틸 아세테이트에서 분쇄함으로써 정제하여, 1-(디페닐포스포릴)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4일)카르바모일)메탄설폰아미드 (9.1 g, 18.40 mmol, 91% 수율)를 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.4 (bs, 1H), 8.14 (s, 1H), 7.88 - 7.83 (m, 4H), 7.63 - 7.53 (m, 6H), 6.96 (s, 1H), 4.99 (d, J = 8.8 Hz, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.71 (t, J = 7.2 Hz, 4H), 2.00 - 1.91 (m, 4H); MS (ESI): m/z (%) = 495.14 (100%) (M+H)+.
중간체-7b (실시예 111):
tert-부틸 (S,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
의 제조
1-(디페닐포스포릴)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)메탄설폰아미드 [중간체 9] (0.5 g, 1.011 mmol)을 N2 분위기 하에 DMF (5 mL)에 용해시켰다. 이를 0°C로 냉각시키고, NaH (0.089 g, 2.224 mmol)를 N2 분위기 하에 0°C에서 첨가하였다. 그 후 아이스 배스를 제거하고, RM을 RT에서 30분 동안 교반하였다. 그 다음, DMF (2.5 mL) 중 tert-부틸 (S)-2-포르밀-2-메틸피롤리딘-1-카르복실레이트 (0.259 g, 1.213 mmol)의 용액을 상기 현탁액에 -20°C에서 적가하였다. 그 다음, RM을 RT로 가온하고, 18시간 동안 추가로 교반하였다. TLC로 소량의 출발 물질이 관찰됨을 확인하였다. RM을 물 (15 mL)로 희석시키고, 수성층을 시트르산 용액으로 산성화하고 고체 침전물을 여과하고 물 (15 mL)로 세척하고, P2O5에서 건조시켰다. 조 생성물을 40% EtOAc : 헥산을 사용하여 컬럼 크로마토그래피에 의해 정제하여 tert-부틸 (S,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트 (0.125 g, 0.255 mmol, 25.3 % 수율)를 얻었다.
중간체-7a (실시예 52)는 또한 tert-부틸 (R)-2-포르밀-2-메틸피롤리딘-1-카르복실레이트를 사용하여 중간체-7b (실시예 111)의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-3a (실시예 10)은 또한 tert-부틸 (R)-2-포르밀피롤리딘-1-카르복실레이트를 사용하여 중간체-7b의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-3b (실시예 61)은 또한 tert-부틸 (S)-2-포르밀피롤리딘-1-카르복실레이트를 사용하여 중간체-7b의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-10a: tert-부틸 2-포르밀아제티딘-1-카르복실레이트의 제조
1-(tert-부틸) 2-메틸 아제티딘-1,2-디카르복실레이트 (European Journal of Medicinal Chemistry, 2000, 35(11), 979-988; Journal of the American Chemical Society (2010), 132(40), 14027-14029) (4.26 gm, 19.79 mmol)의 용액에 건조 DCM (86 mL) 중에서 용액을 얻었다. DIBAL-H (톨루엔 중 26.4 mL의 1.5M, 39.6 mmol)를 -78oC에서 적가하였다. 반응 혼합물을 -78oC에서 2시간 동안 교반한 후 메탄올 (5 mL)로 -78oC 온도에서 중지시켰다. 반응 혼합물을 50% 시트르산 용액으로 pH=4.0까지 산성화하였다. 물 (100 mL) 및 DCM (50 mL)을 첨가하였다. 수성층을 DCM (2 X 80 mL)으로 추출하였다. 합한 유기층을 물 (150 mL), 염수 (10 mL)로 세척하고, Na2SO4로 건조하고, 용매를 증발시켜 생성물 tert-부틸 2-포르밀아제티딘-1-카르복실레이트 (3.4 gm, 18.36 mmol, 93% 수율)를 얻었다.
중간체-10b: tert-부틸 2-포르밀-2-메틸아제티딘-1-카르복실레이트의 제조
중간체-10b는 또한 1-(tert-부틸) 2-메틸 2-메틸아제티딘-1,2-디카르복실레이트를 사용하여 중간체-10a의 합성에 대해 설명된 절차에 따라 제조하였다.
중간체-11a: tert-부틸 (E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)아제티딘-1-카르복실레이트의 제조
0oC에서 DMF (60 mL) 중 tert-부틸 (((디페닐포스포릴)메틸)설포닐)카바메이트 (6.0 gm, 15.17 mmol)의 용액에 NaH (미네랄 오일 중 60 % 분산액) (1.34 gm, 33.4 mmol)를 첨가하였다. 반응을 실온으로 가온되도록 하고, 30분 동안 교반하였다. DMF (35 mL) 중 tert-부틸 2-포르밀아제티딘-1-카르복실레이트 (3.37 g, 18.21 mmol)를 -20oC에서 적가하고, 반응물을 실온으로 가온하고, 밤새 교반하였다. 반응물을 50% 수성 시트르산 (~10 mL)을 사용하여 pH=2.0까지 산성화하고 물 (200 mL)로 희석하고, EtOAc (100 mL x 3)로 추출하였다. 합한 유기층을 물 (150 mL x 3), 염수 (80 mL)로 세척하고, Na2SO4로 건조하고, 농축하고 건조하여 조 생성물을 얻었다. 잔여물을 30% EtOAC: n-헥산을 사용하여 실리카겔 컬럼 크로마토그래피에 의해 정제하여 tert-부틸 (E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)아제티딘-1-카르복실레이트 (1.8 g, 4.97 mmol, 33% 수율)를 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 11.36 (s, 1H), 6.86 (d, J = 15.2 Hz, J = 5.6 Hz, 1H), 6.65 (d, J = 14.8 Hz, 1H), 4.88 - 4.83 (m, 1H), 3.84 - 3.72 (m, 2H), 2.46 - 2.40 (m, 1H), 2.02 - 1.96 (m, 1H), 1.44 (s, 9H), 1.41 (s, 9H); MS (TOF): m/z (%) = 385.2035 (100%) (M+Na), 361.1853 (100%) (M-1).
중간체-11: tert-부틸 (E)-2-(2-설파모일비닐)아제티딘-1-카르복실레이트의 제조
tert-부틸
(E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)아제티딘-1-카르복실레이트 (중간체 11a) (1.8 g, 4.97 mmol)를 DMSO (18 mL)에 용해시키고 85oC로 가열하였다(출발 물질의 소멸은 TLC에 의해 모니터링됨). 반응물을 냉각시키고, 물 (90 mL)에 붓고, EtOAc (40 mL x 4)로 추출하고, Na2SO4로 건조하였다. 용매를 진공에서 농축하고 실리카겔 컬럼 크로마토그래피 (60% EtOAc:n-헥산)에 의해 정제하여 tert-부틸 (E)-2-(2-설파모일비닐)아제티딘-1-카르복실레이트 (2.02 g, 3.74 mmol, 83% 수율)를 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.06 (s, 2H), 6.62 - 6.57 (m, 1H), 6.49 (dd, J = 14.8 Hz, J = 1.2 Hz, 1H), 4.81 - 4.76 (m, 1H), 3.81 - 3.71 (m, 2H), 2.41 - 2.37 (m, 1H), 2.00 - 1.93 (m, 1H), 1.38 (s, 9H),; MS (TOF): m/z (%) = 285.1431 (100%) (M+Na), 261.1290 (100%) (M-1).
중간체-12a: tert-부틸 (E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)-2-메틸아제티딘-1-카르복실레이트의 제조
0oC에서 DMF (45 mL) 중 tert-부틸 (((디페닐포스포릴)메틸)설포닐)카바메이트 (4.5 gm, 11.38 mmol)의 용액에 NaH (미네랄 오일 중 60 % 분산액) (1.00 gm, 25.04 mmol)를 첨가하였다. 반응물을 실온으로 가온되도록 하고 30분 동안 교반하였다. DMF (30 mL) 중 tert-부틸 2-포르밀-2-메틸아제티딘-1-카르복실레이트 (Journal of Medicinal Chemistry, 2014, 57(23), 10044-10057) (2.72 gm, 13.66 mmol)를 -20°C에서 적가하고, 반응물을 실온으로 가온하고 밤새 교반하였다. 반응물을 50% 수성 시트르산을 사용하여 pH=2.0까지 산성화하고 물 (100 mL)로 희석하고, EtOAc (80 mL x 3)로 추출하였다. 합한 유기층을 물 (100 mL x 3), 염수 (50 mL)로 세척하고, Na2SO4로 건조하고, 농축하고 건조하여 조 생성물을 얻었다. 잔여물을 30% EtOAC: n-헥산을 사용하여 실리카겔 컬럼 크로마토그래피에 의해 정제하여 tert-부틸 (E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)-2-메틸아제티딘-1-카르복실레이트 (3.73 g, 9.91 mmol, 87% 수율)를 얻었다. 1 H NMR (400 MHz, DMSO- d 6 ): δ = 11.39 (s, 1H), 6.94 - 6.88 (m, 1H), 6.63 - 6.56 (m, 1H), 3.75 - 3.71 (m, 1H), 3.66 - 3.63 (m, 1H), 2.21 - 2.11 (m, 2H), 1.44 - 1.41 (m, 9H), 1.38 - 136 (m, 9H); MS (ESI): m/z (%) = 399.20 (100%) (M+Na), 375.20 (100%) (M-1).
중간체-12: tert-부틸 (E)-2-메틸-2-(2-설파모일비닐)아제티딘-1-카르복실레이트의 제조
tert-부틸(E)-2-(2-(N-(tert-부톡시카르보닐)설파모일)비닐)-2-메틸아제티딘-1-카르복실레이트 (중간체-12a) (3.73 g, 9.91 mmol)를 DMSO (20 mL)에 용해시키고, 85oC로 가열하였다(출발 물질의 소멸은 TLC에 의해 모니터링됨). 반응물을 냉각시키고, 물 (70 mL)에 붓고, EtOAc (30 mL x 4)로 추출하고, Na2SO4로 건조하였다. 용매를 진공에서 농축시키고, 실리카겔 컬럼 크로마토그래피 (60% EtOAc:n-헥산)에 의해 정제하여 tert-부틸 (E)-2-메틸-2-(2-설파모일비닐)아제티딘-1-카르복실레이트 (2.52 g, 9.12 mmol, 92% yield)를 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.06 (s, 2H), 6.68 - 6.61 (m, 1H), 6.46 - 6.40 (m, 1H), 3.82 - 3.60 (m, 2H), 2.19 - 1.99 (m, 2H), 1.50 (m, 3H), 1.39 - 1.37 (m, 9H); MS (ESI): m/z (%) = 299.10 (100%) (M+Na), 275.05 (100%) (M-1).
실시예-1
(R,E)-2-(1-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드
DCM (2.5 mL) 중 중간체 3 a (1 eq.)의 용액에 TFA (1 eq.)를 0oC에서 첨가하였다. 반응물을 실온(r.t.)으로 가온하고, 3시간 동안 추가 교반하였다. 반응 혼합물을 진공에서 농축하고, 분취(prep.) HPLC에 의해 정제하여 생성물을 얻었다. MeOH (7.0 mL) 중 상기 생성물 (1 eq.)의 용액에 NaHCO3 (1.2 eq.)를 실온에서 첨가하고, 5분 동안 교반하였다. 아세트알데히드 (5 eq.)를 실온에서 첨가하고 2시간 동안 교반하였다. 그 후, 반응 혼합물을 NaBH4 (1.5 eq.)로 조금씩 0oC에서 처리한 다음, 반응 혼합물을 실온으로 가온되도록 하여 밤새 교반하였다. 반응 혼합물을 분취 HPLC에 의해 정제하여 순수한 생성물 (실시예 1)을 얻었다.
대안적으로: DCM (2.5 mL) 중 중간체 3 (1 eq.)의 용액에 TFA (1 eq.)를 0oC에서 첨가하였다. 반응물을 실온(r.t.)으로 가온하고, 3시간 동안 추가 교반하였다. 반응 혼합물을 진공에서 농축하고, 분취 HPLC에 의해 정제하여 생성물을 얻었다. 건조 THF (5.0 mL) 중 상기 생성물 (1 eq.)의 용액에 NaH (1.2 eq.)를 0°C에서 첨가하고, 5분 동안 교반하였다. 에틸 브로마이드 (1.6 eq.)를 첨가하고 14시간 동안 실온에서 교반하였다. 반응 혼합물을 분취 HPLC에 의해 정제하여 순수한 생성물 (실시예 1)을 얻었다.
대안적으로: DCM 중 (R,E)-tert-부틸 2-(2-(N-(tert-부톡시카르보닐)설파모일)-비닐)피롤리딘-1-카르복실레이트 (3.4 g, 9.04 mmol)의 용액에 트리플루오로 아세트산 (15.3 mL)을 첨가하고, 1시간 동안 실온에서 교반하였다. DCM을 증류하고, 과량의 트리메틸아민 (5.23 g, 7.2 mL, 53.1 mmol)을 반응 혼합물에 0°C에서 첨가한 후, 에틸 브로마이드 (1.35 g, 0.926 mL, 12.74 mmol)를 첨가하였다. 조(crude) 혼합물을 (R,E)-2-(1-에틸피롤리딘-2-일)에텐-1-설폰아미드에 제공하였다. 질소 대기 조건 하에 DMF (50 mL) 중 (R,E)-2-(1-에틸피롤리딘-2-일)에텐-1-설폰아미드 (2.11 g, 10.33 mmol)의 용액에 소듐 하이드라이드 (미네랄 오일 중 60%)(0.5 g, 12.39 mmol)를 일 부분으로 첨가하였다. 생성된 현탁액을 1시간 동안 실온에서 추가로 교반하였다. 추가로 4-이소시아나토-1,2,3,5,6,7-헥사히드로-s-인다센 (2 g, 10.05 mmol)을 첨가하고, 반응 혼합물(RM)을 실온에서 16시간 동안 교반하였다. 반응 혼합물을 감압 하에 농축하고, 시트르산으로 산성화하였다. 조 생성물을 분취 HPLC에 의해 정제하여 순수한 생성물 (실시예 1)을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.03 (s, 1H), 6.92 (s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.60-6.54 (m, 1H), 3.27-3.16 (m, 3H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.35-2.33 (m, 2H), 2.09-1.94 (m, 6H), 1.81-1.73 (m, 2H), 1.03 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)+.
당업자의 범위 내에 있는 필요할 수 있는 단계의 적합한 추가 및/또는 삭제를 포함하는, 적절한 출발 물질 및 실시예 1에서 설명된 과정의 적합한 변형을 사용하여, 하기 화합물들을 아날로그 방식으로 제조하였다.
실시예-2
(S,E)-2-(1-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.03 (s, 1H), 6.92 (s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.60-6.54 (m, 1H), 3.27-3.16 (m, 3H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.35-2.33 (m, 2H), 2.09-1.94 (m, 6H), 1.81-1.73 (m, 2H), 1.03 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)+.
실시예-3
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 9.71 (brs, 1H), 7.49 (s, 1H), 6.95 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.36 (dd, J = 7.2 Hz, J = 15.2 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.18 - 3.03 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.14 - 2.07 (m, 4H), 2.03 - 1.80 (m, 6H), 1.70 - 1.60 (m, 1H); MS (ESI): m/z (%) = 376.10 (100%) (M+H)+, 374.05 (100%) (M-1).
실시예-4
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-프로필피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.00 (s, 1H), 6.93 (s, 1H), 6.84 (d, J = 14.8 Hz, 1H), 6.58 (dd, J = 7.6 Hz, J = 15.2 Hz, 1H), 3.15 (s, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.22 (m, 2H), 2.09 - 1.91 (m, 6H), 1.78 - 1.73 (m, 2H), 1.62 - 1.50 (m, 1H), 1.46 - 1.33 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 418.22 (100%) (M+H)+.
실시예-5
(R,E)-2-(1-(시클로프로필메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.42 (brs, 1H), 8.03 (s, 1H), 6.93 (s, 1H), 6.87 (d, J = 15.2 Hz, 1H), 6.62 (dd, J = 7.2 Hz, J = 15.2 Hz, 1H), 3.38 - 3.22 (m, 3H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.60 - 2.57 (m, 1H), 2.30 - 2.05 (m, 1H), 2.04 - 1.91 (m, 5H), 1.87 - 1.71 (m, 2H), 1.70 - 1.50 (m, 1H), 0.91 - 0.67 (m, 1H), 0.53 - 0.35 (m, 2H), 0.18 - 0.09 (m, 2H); MS (ESI): m/z (%) = 430.20 (100%) (M+H)+, 428.11 (100%) (M-1).
실시예-6
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드
DCM (2.5 mL) 중 중간체 3a (1 eq.)의 용액에 TFA (1 eq.)를 0oC에서 첨가하였다. 반응물을 실온으로 가온하고 3시간 동안 추가 교반하였다. 반응 혼합물을 진공에서 농축하고, 분취 HPLC에 의해 정제하여 생성물을 얻었다. 실온에서 MeOH (7.0 mL) 중 상기 생성물 (1 eq.)의 용액에 고체 NaHCO3 (1.2 eq.)를 첨가하고, 5분 동안 교반하였다. 포름알데히드 (37% 용액) (5 eq.)를 실온에서 첨가하고, 2시간 동안 교반하였다. 그 후, 반응 혼합물을 NaBH4 (1.5 eq.)로 조금씩 0oC에서 처리한 다음, 반응 혼합물을 실온으로 가온되게 하여 밤새 교반하였다. 반응 혼합물을 분취 HPLC에 의해 정제하여 순수 생성물울 얻었다.
대안적으로, 실시예 6은 또한 유기 합성 분야의 당업자에게 공지된 통상적인 기술과 함께, 중간체 9 및 (R)-1-메틸피롤리딘-2-카브알데히드를 사용하여 중간체-7b (실시예 111)의 합성에 대해 기재된 절차에 따라 제조하였다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.53 (brs, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.84 (d, J = 15.2 Hz, 1H), 6.53 (dd, J = 7.6 Hz, J = 15.2 Hz, 1H), 3.13 - 3.04 (m, 1H), 3.05 - 2.92 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.28 (m, 1H), 2.26 (s, 3H), 2.05 - 1.91 (m, 5H), 1.79 - 1.72 (m, 2H), 1.59 - 1.54 (m, 1H); MS (ESI): m/z (%) = 390.17 (100%) (M+H)+, 388.07 (30%) (M-1).
실시예-7
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)-피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.55 (bs, 1H), 8.06 (s, 1H), 6.94 (s, 1H), 6.79 - 6.69 (m, 2H), 4.50 - 4.47 (m, 1H), 3.34 - 3.33 (m, 1H), 2.94 (s, 3H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.6 Hz, 4H), 2.11 - 2.07 (m, 2H), 1.95 (quin, J = 7.6 Hz, 4H), 1.88 - 1.85 (m, 1H), 1.80 - 1.79 (m, 2H); MS (ESI): m/z (%) = 454.17 (100%) (M+H)+.
실시예-8
(R,E)-2-(1-아세틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.25 (bs, 1H), 8.07 (s, 1H), 6.95 (s, 1H), 6.73 - 6.67 (m, 1H), 6.63 (d, J = 15.2 Hz, 1H), 4.69 - 4.62 (m, 1H), 3.55 - 3.42 (m, 1H), 2.83 (t, J = 7.2 Hz, 4H), 2.69 (q, J = 7.2 Hz, 4H), 2.21 - 2.09 (m, 1H), 2.01 - 1.95 (m, 6H), 1.85 (s, 3H), 1.82 - 1.72 (m, 2H); MS (ESI): m/z (%) = 418.20 (100%) (M+H)+.
실시예-9
(E)-2-(1-벤질피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.23 (br s, 1H), 8.02 (s, 1H), 7.35 - 7.25 (s, 5H), 6.94 (s, 1H), 6.76 - 6.63 (m, 2H), 3.55 (s, 2H), 2.89 - 2.69 (m, 6H), 2.65 (t, J = 7.2 Hz, 4H), 2.30 - 2.27 (m, 1H), 2.12 - 2.07 (m, 2H), 2.00 - 1.91 (m, 4H), 1.71 - 1.69 (m, 2H), 1.43 - 1.38 (m, 2H); MS (ESI): m/z (%) = 480.23 (100%) (M+H)+.
실시예-10
tert-부틸 (R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d6): δ = 10.42 (s, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.71 - 6.68 (m, 1H), 6.59 (d, J = 14.8 Hz, 1H), 4.45 - 4.38 (m, 1H), 3.29 - 3.27 (m, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 2.30 - 1.93 (m, 5H), 1.78 - 1.71 (m, 3H), 1.39 - 1.33 (m, 9H); MS (ESI): m/z (%) = 498.18 (40%) (M+Na)+, 474.18 (100%) (M-1).
실시예-11
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-메톡시에틸)피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 7.38 (s, 1H), 6.77 (s, 1H), 6.67 (d, J = 15.2 Hz, 1H), 6.04 (dd, J1 = 8.0 Hz, J2 = 15.2 Hz, 1H), 3.37 (t, J = 6.0 Hz, 2H), 3.37 (s, 3H), 3.13 - 3.10 (m, 1H), 2.82 - 2.74 (m, 6H), 2.69 (t, J = 7.2 Hz, 4H), 2.22 - 2.13 (m, 2H), 1.95 - 1.93 (m, 5H), 1.76 - 1.67 (m, 2H), 1.48 - 1.41 (m, 1H); MS (ESI): m/z (%) = 434.19 (100%) (M+H)+.
실시예-12
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(이소프로필설포닐)피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.34 (s, 1H), 6.77 (s, 1H), 6.67 (d, J = 15.2 Hz, 1H), 6.20 - 6.19 (m, 1H), 4.39 (bs, 1H), 3.46 (q, J = 9.6 Hz, 1H), 3.29 - 3.24 (m, 2H), 2.76 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.09 - 2.04 (m, 1H), 1.93 (t, J = 7.2 Hz, 4H), 1.87 (t, J = 8.4 Hz, 4H), 1.73 - 1.69 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H); MS (ESI): m/z (%) = 482.13 (65%) (M+H)+, 504.10 (100%) (M+Na)+;
실시예-13
(R,E)-2-(1-((3-플루오로페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.46 (s, 1H), 8.07 (s, 1H), 7.71 - 7.70 (m, 3H), 7.62 - 7.58 (m, 1H), 6.95 (s, 1H), 6.90 (d, J = 14.8 Hz, 1H), 6.74 (dd, J 1 = 5.6 Hz, J 2 = 15.2 Hz 1H), 4.49 (t, J = 5.6 Hz, 1H), 3.42 - 3.38 (m, 1H), 3.18 - 3.14 (m, 1H), 2.80 (t, J = 7.6 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.96 (quin, J = 7.2 Hz, 4H), 1.76 - 1.60 (m, 3H), 1.55 - 1.52 (m, 1H); MS (ESI): m/z (%) = 534.18 (100%) (M+H)+;
실시예-14
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(피라진-2-카르보닐)피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.46 (s, 1H), 8.95 - 8.88 (m, 1H), 8.78 - 8.65 (m, 1H), 8.70 - 8.57 (m, 1H), 8.04 (s, 1H), 6.93 (s, 1H), 6.76 (d, J = 15.6 Hz, 1H), 6.95 (d, J = 15.2 Hz, 1H), 4.93 - 4.90 (m, 1H), 3.84 - 3.81 (m, 1H), 3.66 - 3.59 (m, 1H), 2.82 (t, J = 8.0 Hz, 4H), 2.66 (t, J = 7.6 Hz, 4H), 2.16 - 1.97 (m, 1H), 1.95 - 1.78 (m, 7H); MS (ESI): m/z (%) = 482.16 (100%) (M+H)+.
실시예-15
(R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복스아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.95 (s, 1H), 6.91 (s, 1H, 6.58 - 6.52 (m, 2H), 5.77 (s, 2H), 4.51 - 4.48 (m, 1H), 3.25 - 3.21 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 6.8 Hz, 4H), 2.00 - 1.91 (m, 6H), 1.81 - 1.69 (m, 3H); MS (ESI): m/z (%) = 419.16 (100%) (M+H)+.
실시예-16
(R,E)-2-(1-(시클로프로판카르보닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 8.11 (d, J = 14.4 Hz, 1H), 6.96 (s, 1H), 6.87 - 6.52 (m, 2H), 4.97 - 4.65 (m, 1H), 3.76 - 3.61 (m, 1H), 3.41 - 3.32 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.67 (q, J = 6.0 Hz, 4H), 2.17 - 2.16 (m, 1H), 2.02 - 1.95 (m, 5H), 1.88 - 1.74 (m, 3H), 1.76 - 0.69 (m, 2H), 0.66 - 0.59 (m, 2H); MS (ESI): m/z (%) = 444.15 (100%) (M+H)+.
실시예-17
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2,2,2-트리플루오로아세틸)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H), 8.03 (s, 1H), 6.94 (s, 1H), 6.76 - 6.67 (m, 2H), 4.80 (bs, 1H), 3.75 (bs, 1H), 3.67 - 3.54 (m, 1H), 2.80 (t, J = 7.6 Hz, 4H), 2.67 (t, J = 6.4 Hz, 4H), 2.15 - 2.5 (m, 1H), 2.00 - 1.91 (m, 6H), 1.81 - 1.76 (m, 1H); MS (ESI): m/z (%) = 472.14 (100%) (M-H)+.
실시예-18
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-(메틸티오)에틸)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.38 (s, 1H), 8.06 (s, 1H), 6.95 (s, 1H), 6.91 (d, J = 14.8 Hz, 1H), 6.68 (d, J = 15.2 Hz, 1H), 3.21 - 3.12 (m, 2H), 2.81 (t, J = 7.2 Hz, 5H), 2.68 (t, J = 7.2 Hz, 5H), 2.46 - 2.40 (m, 1H), 2.33 - 2.24 (m, 1H), 2.09 - 1.91 (m, 9H), 1.74 - 1. 70 (m, 2H), 1.54 - 1.49 (m, 1H); MS (ESI): m/z (%) = 450.14 (100%) (M+H)+.
실시예-19
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2,2,2-트리플루오로에틸)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.91 (s, 1H), 6.88 (s, 1H), 6.76 (d, J = 15.2 Hz, 1H), 6.41 (dd, J 1 = 7.2 Hz, J 2, 14.8, 1H), 3.34 - 3.21 (m, 1H), 3.16 - 3.09 (m, 2H), 2.78 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.59 - 2.54 (m, 1H), 2.02 - 1.91 (m, 6H), 1.80 - 1.75 (m, 2H), 1.57 - 1.48 (m, 1H); MS (ESI): m/z (%) = 458.15 (100%) (M+H)+.
실시예-20
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소부틸피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.4 (brs, 1H), 8.00 (s, 1H), 6.92 (s, 1H), 6.80 (d, J = 15.2 Hz, 1H), 6.56 (dd, J = 15.2 Hz , J = 6.8 Hz, 1H), 3.12 - 3.00 (m, 3H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.25 - 2.14 (m, 2H), 2.10 - 2.04 (m, 2H), 1.99 - 1.91 (m, 4H), 1.76 - 1.65 (m, 2H), 1.55 - 1.48 (m, 1H), 0.85 (t, J = 6.8 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 432.21 (100%) (M+H)+.
실시예-21
(R,E)-2-(1-(에틸설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.39 (brs, 1H), 8.01 (s, 1H), 7.38 (s, 1H), 6.77 (d, J = 15.2 Hz, 1H), 6.68 (dd, J = 15.2 Hz , J = 5.2 Hz, 1H), 4.63 - 4.39 (m, 1H), 3.38 - 3.33 (m, 2H), 3.09 - 2.97 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.15 - 2.04 (m, 1H), 2.00 - 1.91 (m, 4H), 1.88 - 1.77 (m, 3H), 1.19 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 468.12 (100%) (M+H)+.
실시예-22
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소프로필피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.23 (brs, 1H), 7.96 (s, 1H), 6.92 (s, 1H), 6.89 (d, J = 15.2 Hz, 1H), 6.61 (d, J = 15.2 Hz, J = 7.2 Hz, 1H), 2.98 - 2.85 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.51 - 2.50 (m, 1H), 2.02 - 1.91 (m, 6H), 1.75 - 1.73 (m, 2H), 1.61 - 1.56 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.21 (100%) (M+H)+, 416.18 (100%) (M-1).
실시예-23
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(3-(메틸설포닐)프로필)피롤리딘-2-일)에텐설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.37 (brs, 1H), 8.08 (s, 1H), 6.95 (s, 1H), 6.82 (d, J = 14.8 Hz, 1H), 6.61 (d, J = 14.8 Hz, J = 7.2 Hz, 1H), 3.13 - 3.06 (m, 3H), 2.98 - 2.91 (m, 1H), 2.86 (s, 3H), 2.67 (t, J = 7.2 Hz, 4H), 2.81 (t, J = 7.2 Hz, 4H), 2.33 - 2.28 (m, 1H), 2.27 - 2.20 (m, 1H), 2.03 - 1.91 (m, 6H), 1.83 - 1.72 (m, 4H), 1.57 - 1.50 (m, 1H); MS (ESI): m/z (%) = 496.16(100%) (M+H)+, 494.15 (100%) (M-1).
실시예-24
(R,E)-2-(1-벤조일피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.41 (brs, 1H), 8.03 (s, 1H), 7.54 - 7.30 (m, 5H), 6.93 (s, 1H), 6.80 - 6.50 (m, 2H), 4.85 - 4.49 (m, 1H), 3.62 - 3.36 (m, 2H), 2.78 (t, J = 6.8 Hz, 4H), 2.66 (t, J = 6.8 Hz, 4H), 2.19 - 2.08 (m, 1H), 1.94 - 1.90 (m, 4H), 1.82 - 1.76 (m, 3H); MS (ESI): m/z (%) = 480.17 (100%) (M+H)+, 478.15 (100%) (M-1).
실시예-25
(R,E)-N-((2-(1-벤조일피롤리딘-2-일)비닐)설포닐)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)벤즈아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.61 - 7.52 (m, 2H), 7.47 - 7.32 (m, 8H), 7.22- 7.09 (m, 1H), 6.97 (s, 1H), 6.56 (d, J = 14.4 Hz, 1H), 6.31 (d, J = 14.4 Hz, 1H), 4.76 - 4.37 (m, 1H), 3.78- 3.42 (m, 1H), 2.84 - 2.67 (m, 8H), 2.10 - 2.05 (m, 1H), 1.95 - 1.91 (m, 4H), 1.84 - 1.76 (m, 3H), 1.68 - 1.64 (m, 1H); MS (ESI): m/z (%) = 584.19 (100%) (M+H)+, 606.17(50%) (M+Na), 582.17 (10%) (M-1).
실시예-26
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.54 (s, 1H), 6.81 (s, 1H), 6.70 (d, J = 15.2 Hz, 1H), 6.33 - 6.26 (m, 1H), 3.53 - 3.46 (m, 2H), 3.15 - 3.00 (m, 3H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.03 - 1.81 (m, 7H), 1.62 - 1.43 (m, 1H); MS (ESI): m/z (%) = 390.16 (100%) (M+H)+, 388.14(100%) (M-1).
실시예-27
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티오펜-3-카르보닐)피롤리딘-2-일)에텐설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.36 (brs, 1H), 8.01 (s, 1H), 7.58 - 7.48 (m, 1H), 7.36 - 7.22 (m, 1H), 6.93 (s, 1H), 6.81 - 6.56 (m, 2H), 4.83 - 4.74 (m, 1H), 3.78 - 3.67 (m, 1H), 3.66 - 3.52 (m, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 6.8 Hz, 4H), 2.15 - 1.76 (m, 8H); MS (ESI): m/z (%) = 486.13 (100%) (M+H)+, 484.11 (100%) (M-1).
실시예-28
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 메탄 설포네이트
절차: EtOH (2.0 mL) 중 (R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 (0.105 g, 0.28 mmol)의 용액에 메탄설폰산 (27 mg, 0.280 mmol)을 실온에서 첨가하였다. 반응물을 1시간 동안 환류시킨 다음, 실온으로 냉각시켰다. 침전물이 형성된 후, Buchner 깔때기를 통해 여과하고, 진공에서 건조하여 생성물을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.59 (brs, 1H), 9.05 (brs, 2H), 8.27 (s, 1H), 7.13 (d, J = 15.2 Hz, 1H), 6.97 (s, 1H), 6.90 - 6.85 (m, 1H), 4.32 - 4.30 (m, 1H), 3.32 - 3.12 (m, 2H), 3.99- 3.78 (m, 4H), 3.75 - 3.66 (m, 4H), 2.37 (s, 1H), 2.28 - 2.12 (m, 1H), 2.10 - 1.88 (m, 6H), 1.27 - 1.22(m, 1H); MS (ESI): m/z (%) = 376.10 (100%) (M+H)+.
실시예-29
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 말리에이트
절차: - EtOH (4.0 mL) 중 (R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 (0.2 g, 0.533 mmol)의 용액에 말레산 (0.124 g, 1.07 mmol)을 실온에서 첨가하였다. 반응물을 30분 동안 환류시킨 다음, 실온으로 냉각하였다. 침전물이 형성된 후, Buchner 깔때기를 통해 여과하고, 진공에서 건조하여 생성물을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 9.06 (brs, 1H), 8.15 (s, 1H), 7.12 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 6.87 - 6.82 (m, 1H), 6.03 (s, 2H), 4.29- 4.03 (m, 4H), 3.57 - 3.23 (m, 2H), 2.98 - 2.83 (m, 4H), 2.85 - 2.69 (m, 4H), 2.26 - 2.10 (m, 1H), 2.09 - 1.83 (m, 6H), 1.82 - 1.63 (m, 1H); MS (ESI): m/z (%) = 376.15 (100%) (M+H)+.
실시예-30
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 9.70 (brs, 1H), 7.94 (s, 1H), 6.83 (s, 1H), 6.36 (dd, J = 11.6 Hz, J = 1.6 Hz, 1H), 5.82 (dd, J = 11.2 Hz, J = 6.0 Hz, 1H), 4.95 - 4.94 (m, 1H), 3.17 - 3.03 (m, 1H), 2.99 - 2.89 (m, 1H), 2.79 - 2.63 (m, 9H), 2.03 - 1.76 (m, 8H); MS (ESI): m/z (%) = 376.16 (60%) (M+H)+.
실시예-31
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-3-(피롤리딘-2-일)프로프-1-엔-1-설폰아미드
절차: - DCM (2.5 mL) 중 상응하는 N-Boc 유도체 (0.20 g, 0.408 mmol)의 용액에 TFA (0.315 mL, 4.08 mmol)를 0oC에서 첨가하였다. 반응물을 실온으로 가온하고, 3시간 동안 추가 교반하였다. 반응 혼합물을 진공에서 농축하고, 분취 HPLC에 의해 정제하여 생성물을 얻었다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.54 (s, 1H), 6.80 (s, 1H), 6.69 (d, J = 15.2 Hz, 1H), 6.29 - 6.25 (m, 1H), 3.52 - 3.44 (m, 2H), 3.17 - 3.02 (m, 3H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.01 - 1.76 (m, 8H), 1.53 - 1.50 (m, 1H); MS (ESI): m/z (%) = 390.16 (100%) (M+H)+.
실시예-32
(R,E)-2-(1-(시클로헥실설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.4 (brs, 1H), 8.04 (s, 1H), 6.94 (s, 1H), 6.78 (d, J = 15.2 Hz, 1H), 6.69 (dd, J = 15.2 Hz, J = 6.0 Hz, 1H), 4.57 - 4.53 (m, 1H), 3.45 - 3.39 (m, 1H), 3.31 - 3.27 (m, 1H), 3.14 - 3.08 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.17 - 2.09 (m, 1H), 2.00 - 1.91 (m, 5H), 1.88 - 1.60 (m, 5H), 1.55 - 1.52 (m, 1H), 1.40- 1.00 (m, 6H); MS (ESI): m/z (%) = 522.20 (100%) (M+H)+, 544.25 (100%) (M+Na), 520.15 (100%) (M-1).
실시예-33
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.85 (s, 1H), 6.84 (s, 1H), 6.52 (dd, J = 11.2 Hz, J = 1.2 Hz, 1H), 5.84 (dd, J = 11.2 Hz, J = 8.0 Hz, 1H), 4.54 - 4.53 (m, 1H), 3.24- 3.18 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.56 (s, 3H), 2.33 - 2.18 (m, 1H), 1.99 - 1.91 (m, 8H), 1.85 - 1.70 (m, 1H); MS (ESI): m/z (%) = 390.20 (100%) (M+H)+, 388 (100%) (M-1).
실시예-34
(R,E)-2-(1-(시클로헥실메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.38 (brs, 1H), 8.06 (s, 1H), 6.94 (s, 1H), 6.82 (d, J = 14.8 Hz, 1H), 6.62 (dd, J = 15.2 Hz, J = 6.8 Hz, 1H), 3.00 - 3.17 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.40 - 2.28 (m, 1H), 2.26 - 2.13 (m, 1H), 2.12- 1.90 (m, 6H), 1.89 - 1.82 (m, 1H), 1.81 - 1.67 (m, 2H), 1.66 - 1.47 (m, 5H), 1.45- 1.30 (m, 1H), 1.28 - 0.92 (m, 3H), 0.78 - 0.69 (m, 2H); MS (ESI): m/z (%) = 472.29 (100%) (M+H)+.
실시예-35
(R,E)-2-(1-시클로헥실피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.38 (brs, 1H), 8.01 (s, 1H), 6.92 (s, 1H), 6.85 (d, J = 15.2 Hz, 1H), 6.65 (dd, J = 14.4 Hz, J = 6.4 Hz, 1H), 3.90 - 3.62 (m, 1H), 3.09 - 2.96 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.70 - 2.67 (m, 5H), 1.99 - 1.91 (m, 6H), 1.83 - 1.63 (m, 7H), 1.58 - 1.50 (m, 1H), 1.27- 1.02 (m, 5H); MS (ESI): m/z (%) = 458.29 (100%) (M+H)+.
실시예-36
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(1-메틸피페리딘-4-일)피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.46 (s, 1H), 7.29 (s, 1H), 6.77 (s, 1H), 6.64 (d, J = 15.2 Hz, 1H), 6.11 (dd, J = 15.2 Hz, J = 8.0 Hz, 1H), 3.35 - 3.30 (m, 1H), 2.84- 2.80 (m, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.72 - 2.68 (m, 5H), 2.34 - 2.29 (m, 1H), 2.09 (s, 3H), 1.95 - 1.88 (m, 4H), 1.85 - 1.77 (m, 4H), 1.76 - 1.60 (m, 4H), 1.50- 1.35 (m, 3H); MS (ESI): m/z (%) = 473.32 (100%) (M+H)+.
실시예-37
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소프로필피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.14 (brs, 1H), 7.73 (s, 1H), 6.85 (s, 1H), 6.59 (d, J = 11.2 Hz, 1H), 6.04 - 5.99 (m, 1H), 4.91 - 4.89 (m, 1H), 3.48- 3.45 (m, 1H), 3.26- 3.20 (m, 1H), 3.17- 3.01 (m, 1H), 2.78 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.25 - 2.18 (m, 1H), 1.97 - 1.85 (m, 6H), 1.75 - 1.66 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.17 (t, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.23 (100%) (M+H)+, 416.21 (100%) (M-1).
실시예-38
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.30 (brs, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.85 (d, J = 15.2 Hz, 1H), 6.70 (dd, J = 14.8 Hz, J = 6.4 Hz, 1H), 3.83 - 3.73 (m, 2H), 3.69 - 3.59 (m, 1H), 3.23 - 3.15 (m, 2H), 3.03 - 2.91 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.58 - 2.53 (m, 2H), 2.00 - 1.91 (m, 5H), 1.71 - 1.62 (m, 3H), 1.58 - 1.52 (m, 2H), 1.42 - 1.33 (m, 2H); MS (ESI): m/z (%) = 460.30 (100%) (M+H)+.
실시예-39
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(옥세탄-3-일)피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.41 (brs, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.83 (d, J = 14.8 Hz, 1H), 6.61 (dd, J = 15.2 Hz, J = 8.0 Hz, 1H), 4.51 - 4.44 (m, 2H), 4.43 - 4.38 (m, 2H), 3.81 - 3.74 (m, 1H), 3.23 - 3.17 (m, 1H), 3.00 - 2.95 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.41 - 2.33 (m, 1H), 2.01 - 1.91 (m, 5H), 1.78 - 1.71 (m, 2H), 1.62 - 1.55 (m, 1H); MS (ESI): m/z (%) = 432.22 (100%) (M+H)+.
실시예-40
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-티오피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.32 (brs, 1H), 8.06(s, 1H), 6.95 (s, 1H), 6.84 (d, J = 14.8 Hz, 1H), 6.64 (dd, J = 14.8 Hz, J = 6.4 Hz, 1H), 3.71 - 3.58 (m, 1H), 2.98 - 2.87 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.63 - 2.58 (m, 2H), 2.54 - 2.51 (m, 2H), 2.48 - 2.38 (m, 2H), 2.13 - 2.01 (m, 1H), 1.99 - 1.89 (m, 6H), 1.76 - 1.62 (m, 2H), 1.58 - 1.45 (m, 3H); MS (ESI): m/z (%) = 476.24 (100%) (M+H)+.
실시예-41
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티아졸-2-일메틸)피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.33 (brs, 1H), 8.08 (s, 1H), 7.71 (d, J = 3.2 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H), 6.92 - 6.86 (m, 2H), 6.70 (dd, J = 15.2 Hz, J = 6.8 Hz, 1H), 4.04 (d, J = 14.8 Hz, 1H), 3.78 (d, J = 14.8 Hz, 1H), 3.44 - 3.39 (m, 1H), 3.07 - 3.02 (m, 1H), 2.77 (t, J = 6.8 Hz, 4H), 2.61 (t, J = 6.8 Hz, 4H), 2.43 - 2.33 (m, 1H), 2.08 - 1.97 (m, 1H), 1.96 - 1.87 (m, 4H), 1.80 - 1.74 (m, 2H), 1.63- 1.57 (m, 1H); MS (ESI): m/z (%) = 473.19 (100%) (M+H)+
실시예-42
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-4-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.55 (s, 1H), 8.78 (s, 1H), 8.26 (s, 2H), 6.95 (s, 1H), 6.79 - 6.70 (m, 2H), 3.29 (d, J = 11.2 Hz, 2H), 2.80 (t, J = 6.8 Hz, 4H), 2.66 (t, J = 6.4 Hz, 4H), 1.95 (t, J = 6.8 Hz, 4H), 1.90 (d, J = 13.2 Hz, 2H); MS (ESI): m/z (%) = 390.20 (100%) (M+H)+.
실시예-43
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피페리딘-4-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.80 (s, 1H), 6.86 (s, 1H), 6.64 (s, 1H), 6.60 (d, J = 16.4 Hz, 1H), 6.48 (dd, J 1 = 6.0 Hz, J 2 = 15.2 Hz 1H), 3.03 - 2.99 (m, 3H), 2.78 (t, J = 7.6 Hz, 4H), 2.68 (t, J = 7.6 Hz, 4H), 2.38 (s, 3H), 2.36 - 2.24 (m, 2H), 1.94 (t, J = 7.2 Hz, 4H), 1.77 - 1.74 (m, 2H), 1.47 - 1.37 (m, 2H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)+.
실시예-44
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피페리딘-4-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.37 (bs, 1H), 8.11 (s, 1H), 6.96 (s, 1H), 6.78 - 6.7 (m, 2H), 3.57 (d, J = 12.0 Hz, 2H), 2.85 (s, 3H), 2.81 (t, J = 7.2 Hz, 4H), 2.75 - 2.67 (m, 6H), 1.97 (t, J = 7.2 Hz, 4H), 1.82 (d, J = 11.6 Hz, 2H), 1.45 - 1.37 (m, 2H); MS (ESI): m/z (%) = 468.12 (100%) (M+H)+.
실시예-45
(E)-2-(1-아세틸피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.38 (bs, 1H), 8.04 (s, 1H), 6.94 (s, 1H), 6.64 (dd, J 1 = 5.6 Hz, J 2 = 15.6 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 4.33 (d, J = 13.3 Hz, 1H), 3.81 (d, J = 14.4 Hz, 1H), 3.06 (t, J = 12.0 Hz, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.63 - 2.56 (m, 2H), 2.00 - 1.91 (m, 7H), 1.72 (t, J = 15.6 Hz, 2H), 1.35 - 1.24 (m, 1H), 1.21 - 1.11 (m, 1H); MS (ESI): m/z (%) = 432.17 (100%) (M+H)+.
실시예-46
tert-부틸(E)-4-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-피페리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.37 (bs, 1H), 8.05 (s, 1H), 6.96 (s, 1H), 6.8 (dd, J 1 = 6.0 Hz, J 2 = 15.2 Hz, 1H), 6.69 (d, J = 15.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 2H), 2.81 (t, J = 7.2 Hz, 6H), 2.66 (t, J = 6.8 Hz, 4H), 1.97 (t, J = 7.2 Hz, 4H), 1.71 (d, J = 11.6 Hz, 2H), 1.39 (s, 9H), 1.23 - 1.17 (m, 3H); MS (ESI): m/z (%) = 488.18 (100%) (M-H)+.
실시예-47
(E)-2-(1-에틸피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.87 (s, 1H), 6.94 (s, 1H), 6.65 (d, J = 15.6 Hz, 1H), 6.52 (dd, J 1 = 6.0 Hz, J 2 = 15.2 Hz, 1H), 3.16 (d, J = 11.6 Hz, 3H), 2.79 (t, J = 7.2 Hz, 4H), 2.73 - 2.67 (m, 6H), 1.98 - 1.91 (m, 5H), 1.82 - 1.75 (m, 3H), 1.52 - 1.44 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H), MS (ESI): m/z (%) = 418.18 (100%) (M+H)+, 416.17 (100%) (M-1)-.
실시예-48
(R,E)-2-(1-에틸피롤리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.95 (s, 1H), 6.43 (s, 1H), 6.60 (d, J = 14.4 Hz, 1H), 6.55 - 6.45 (m, 1H), 3.18 (d, J = 4.8Hz, 2H), 3.05 - 2.95 (m, 4H), .2.79 (t, J = 7.2 Hz, 4H), 2.73 - 2.67 (m, 5H), 1.95 (t, J = 7.2 Hz, 4H), 1.55 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 7.2 Hz, 2H); MS (ESI): m/z (%) = 404.18 (100%) (M+H)+.
실시예-49
(R,E)-1,1-디에틸-3-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)피롤리딘-1-이움 브로마이드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.27 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 6.27 (dd, J 1 = 6.8 Hz, J 2 = 15.6 Hz, 1H), 5.59 (bs, 1H), 4.12 (s, 1H), 3.78 - 3.72 (m, 2H), 3.62 (t, J = 7.6Hz, 1H), 3.54 (t, J = 8.0 Hz, 1H), 3.41 - 3.36 (m, 2H), 3.30 - 3.24 (m, 2H), 2.76 - 2.69 (m, 8H), 2.33 - 2.25 (m, 1H), 1.93 - 2.90 (m, 4H), 1.20 (t, J = 6.8 Hz, 6H); MS (ESI): m/z (%) = 432.20 (100%) (M)+.
실시예-50
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-3-일)에텐-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.41 (s, 1H), 6.78 (s, 1H), 6.64 (d, J = 15.6 Hz, 1H), 6.23 (dd, J 1 = 7.6 Hz, J 2 = 15.2 Hz, 1H), 3.18 - 3.14 (m, 1H), 2.99 - 2.95 (m, 1H), 2.76 (t, J = 7.6 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.00 - 1.97 (m, 2H), 1.95 (t, J = 7.6 Hz, 4H), 1.90 - 1.88 (m, 2H), 1.76 - 1.54 (m, 1H); MS (ESI): m/z (%) = 376.15 (100%) (M+H)+.
실시예-51
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.56 (s, 1H), 6.91 (d, J = 15.6 Hz, 1H), 6.82 (s, 1H), 6.52 (d, J = 15.2 Hz, 1H), 3.23 - 3.19 (m, 2H), 3.14 - 3.07 (m, 1H), 2.77 (t, J = 7.6 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.96 - 1.87 (m, 8H), 1.79 - 1.74 (m, 1H), 1.34 (s, 3H); MS (ESI): m/z (%) = 390.14 (100%) (M+H)+.
실시예-52
tert-부틸(R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.41 (s, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.87 (d, J = 16.0 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 3.38 - 3.32 (m, 2H), 2.82 (t, J = 7.6 Hz, 4H), 2.75 (t, J = 7.2 Hz, 4H), 1.95 (t, J = 7.2 Hz, 5H), 1.86 - 1.69 (m, 3H), 1.48 - 1.41 (m, 3H), 1.34 (s, 9H); MS (ESI): m/z (%) = 488.16 (100%) (M-H)+.
실시예-53
(R,E)-2-(1-아세틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.40 (s, 1H), 8.06 (s, 1H), 6.96 (s, 1H), 6.91 (d, J = 15.6 Hz, 1H), 6.58 (d, J = 15.2 Hz, 1H), 3.57 - 3. 50 (m, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.01 - 1.88 (m, 8H), 1.82 - 1. 74 (m, 3H), 1.52 (s, 3H); MS (ESI): m/z (%) = 432.09 (100%) (M+H)+.
실시예-54
(R,E)-1,1-디에틸-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)-2-메틸피롤리딘-1-이움 브로마이드;
1H NMR (400 MHz, DMSO-d 6 ): δ = 6.88 (s, 1H), 6.65 (d, J = 15.6 Hz, 1H), 6.21 - 6.15 (m, 1H), 2.84 - 2.75 (m, 6H), 2.68 - 2.58 (m, 3H), 2.35 - 2.29 (m, 2H), 1.96 - 1.91 (m, 7H), 1.76 - 1.59 (m, 4H), 0.97 (t, J = 7.2 Hz, 6H), 0.88 (s, 3H); MS (ESI): m/z (%) = 446.19 (100%) (M+H)+.
실시예-55
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(메틸설포닐)-피롤리딘-2-일)에텐-1-설폰아미드;:
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.43 (bs, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.90 (d, J = 15.2 Hz, 1H), 6.72 (d, J = 15.2 Hz, 1H), 3.44 (t, J = 6.0 Hz, 2H), 2.95 (s, 3H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.07 - 1.83 (m, 7H), 1.79 - 1.74 (m, 1H), 1.24 (s, 3H), MS (ESI): m/z (%) = 468.11 (100%) (M+H)+.
실시예-56
(R,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
1H NMR (400 MHz, DMSO-d 6 ): δ = 8.04 (s, 1H), 6.93 (s, 1H), 6.74 (d, J = 15.6 Hz, 1H), 6.65 (d, J = 15.2 Hz, 1H), 2.93 - 2.86 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.19 (s, 3H), 1.99 - 1.91 (m, 5H), 1.80 - 1.69 (m, 4H), 1.13 (s, 3H), MS (ESI): m/z (%) = 404.16 (100%) (M+H)+.
대안적으로, 실시예 56은 또한 유기 합성 분야의 당업자에게 공지된 통상적인 기술과 함께, 중간체 9 및 (R)-1,2-디메틸피롤리딘-2-카브알데히드를 사용하여 중간체-7b (실시예 111)의 합성에 대해 기재된 절차에 따라 제조하였다.
실시예-57
(R,E)-2-(1-에틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 8.82 (bs, 1H), 6.96 (s, 1H), 6.92 (d, J = 9.6 Hz, 1H), 6.41 (m, 1H), 3.60 - 3.51 (m, 2H), 3.22 - 3.17 (m, 2H), 2.80 - 2.73 (m, 5H), 2.61 (t, J = 7.2 Hz, 4H), 1.97 - 1.93 (m, 6H), 1.84 - 1.80 (m, 1H), 1.53 (s, 3H), 0.90 (t, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.18 (100%) (M+H)+;
실시예-58
(R,E)-2-(1-(시클로프로필메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.39 (s, 1H), 8.06 (s, 1H), 6.94 (s, 1H), 6.75 (d, J = 15.6 Hz, 1H), 6.69 (d, J = 15.6 Hz, 1H), 3.18 - 3.13 (m, 1H), 2.80 (t, J = 7.2 Hz, 5H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.11 (m, 2H), 1.94 (t, J = 7.2 Hz, 4H), 1.80 - 1.71 (m, 4H), 1.12 (s, 3H), 0.86 - 0.79 (m, 1H), 0.42 (quin, J = 8.8 Hz, 2H), 0.05 - 0. 04 (m, 2H); MS (ESI): m/z (%) = 444.17 (100%) (M+H)+.
실시예-59
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-설폰아미드
1H NMR (400 MHz, DMSO): δ = 8.75 (bs, 1H), 7.50 (s, 1H), 6.95 (d, J=15.6Hz, 1H), 6.80 (s, 1H), 6.39-6.33 (m, 1H), 4.08-4.02 (m, 1H), 3.16-4.11 (m, 2H), 2.77 (t, J=7.2Hz, 4H), 2.71 (t, J=7.2Hz, 4H), 2.12-2.08 (m, 1H), 1.96-1.85 (m, 6H), 1.68-1.62 (m, 1H); MS (ESI): m/z (%) = 376.16 (100%) (M+H)+.
실시예-60
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO): δ = 8.00 (s, 1H), 6.93 (s, 1H), 6.85 (d, J=15.2Hz, 1H), 6.58-6.52 (m, 1H), 3.12-3.04 (m, 2H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.36-2.31 (m, 1H), 2.27 (s, 3H), 2.08-1.91 (m, 5H), 1.80-1.72 (m, 2H), 1.70-1.50 (m, 1H); MS (ESI): m/z (%) = 390.17 (100%) (M+H)+.
실시예-61
(S,E)-tert-부틸2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO): δ = 10.42 (bs, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.71-6.67 (m, 1H), 6.61-6.57 (m, 1H), 4.45-4.38 (m, 1H), 3.29-3.25 (m, 2H), 2.81 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.09-1.93 (m, 5H), 1.78-1.71 (m, 3H), 1.33 (s, 9H); MS (ESI): m/z (%) = 498.18 (80%) (M+Na)+.
실시예-62
(S,E)-2-(1-(시클로프로필메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.32 (bs, 1H), 8.02 (bs, 1H), 6.93 (s, 1H), 6.86 (d, J=14.8Hz, 1H), 6.64 - 6.50 (m, 1H), 3.50 - 3.20 (m, 3H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.61 - 2.56 (m, 1H), 2.15 - 1.91 (m, 6H), 1.85 - 1.78 (m, 2H), 1.62 - 1.53 (m, 1H), 0.86 - 0.80 (m, 1H), 0.50 - 0.30 (m, 2H), 0.15 - 0.14 (m, 2H); MS (ESI): m/z (%) = 430.19 (100%) (M+H)+.
실시예-63
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(피리딘-3-일설포닐)-피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.40 (bs, 1H), 9.02 (d, J=2.0Hz, 1H), 8.90 - 8.88 (m, 1H), 8.29 - 8.26 (m, 1H), 8.04 (s, 1H), 7.68 - 7.65 (m, 1H), 6.94 - 6.87 (m, 2H), 6.72 - 6.67 (m, 1H), 4.52 - 4.49 (m, 1H), 3.44 - 3.42 (m, 1H), 3.21 - 3.15 (m, 1H), 2.80 (t, J=7.2Hz, 4H), 2.69 (t, J=7.2Hz, 4H), 1.99 - 1.91 (m, 4H), 1.76 - 1.65 (m, 4H); MS (ESI): m/z (%) = 517.11 (100%) (M+H)+.
실시예-64
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO): δ = 9.50 (bs, 1H), 7.48 (bs, 1H), 7.17 - 7.05 (m, 3H), 6.99 - 6.88 (m, 1H), 6.43 (bs, 1H), 4.15 - 3.90 (m, 1H), 3.20 - 3.00 (m, 4H), 2.15 - 2.00 (m, 1H), 1.99 - 1.80 (m, 3H), 1.79 - 1.60 (m, 1H), 1.20 - 1.00 (m, 12H); MS (ESI): m/z (%) = 380.16 (100%) (M+H)+.
실시예-65
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-에틸피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.60 (bs, 1H), 7.86 (s, 1H), 7.27 - 7.23 (m, 1H), 7.15 - 7.13 (m, 2H), 6.84 (d, J=15.2Hz, 1H), 6.66 - 6.61 (m, 1H), 3.32 - 3.02 (m, 4H), 2.75 - 2.60 (m, 1H), 2.41 - 2.25 (m, 2H), 2.05 - 1.96 (m, 1H), 1.90 - 1.70 (m, 2H), 1.65 - 1.45 (m, 1H), 1.12 - 1.11 (m, 12H), 1.01 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 408.19 (100%) (M+H)+.
실시예-66
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-(메틸설포닐)피롤리딘-2-일)에텐-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 7.81 (s, 1H), 7.25 - 7.21 (m, 1H), 7.13 - 7.11 (m, 2H), 6.75 - 6.64 (m, 2H), 4.46 (s, 1H), 3.29 - 3.24 (m, 1H), 3.10 - 3.03 (m, 2H), 2.93 (s, 3H), 2.09 - 2.04 (m, 1H), 1.89 - 1.83 (m, 1H), 1.77 - 1.73 (m, 3H), 1.12 - 1.11 (m, 12H); MS (ESI): m/z (%) = 458.15 (100%) (M+H)+.
실시예-67
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 7.69 (s, 1H), 7.22 - 7.18 (m, 1H), 7.11 - 7.09 (m, 2H), 6.75 (d, J=15.2Hz, 1H), 6.55 - 6.30 (m, 1H), 3.12 - 2.99 (m, 3H), 2.79 - 2.76 (m, 1H), 2.23 - 2.18 (m, 4H), 2.00 - 1.95 (m, 1H), 1.76 - 1.68 (m, 2H), 1.54 - 1.49 (m, 1H), 1.11 - 1.09 (m, 12H); MS (ESI): m/z (%) = 394.19 (100%) (M+H)+.
실시예-68
(S,E)-2-(1-아세틸피롤리딘-2-일)-N-((2,6-디이소프로필페닐)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.55 (bs, 1H), 7.89 - 7.86 (m, 1H), 7.28 - 7.23 (m, 1H), 7.15 - 7.13 (m, 2H), 6.76 - 6.69 (m, 1H), 6.63 - 6.53 (m, 1H), 4.68 - 4.61 (m, 1H), 3.52 - 3.39 (m, 1H), 3.08 - 3.02 (m, 2H), 1.97 (s, 3H), 1.93 - 1.70 (m, 5H), 1.13 - 1.11 (m, 12H); MS (ESI): m/z (%) = 422.18 (100%) (M+H)+.
실시예-69
(S,E)-2-(1-아세틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.30 (bs, 1H), 8.11 - 8.05 (m, 1H), 6.95 (s, 1H), 6.78 - 6.56 (m, 2H), 4.72 - 4.62 (m, 1H), 3.57 - 3.35 (m, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.67 (q, J = 7.2 Hz, 4H), 1.99 - 1.95 (m, 6H), 1.85 (s, 3H), 1.84 - 1.71 (m, 2H); MS (ESI): m/z (%) = 418.16 (100%) (M+H)+.
실시예-70
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-카르보닐)피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.40 (bs, 1H), 8.03 (s, 1H), 6.94 - 6.93 (m, 1H), 6.74 - 6.49 (m, 2H), 6.64 - 6.50 (m, 1H), 4.84 - 4.65 (m, 1H), 3.87 - 3.78 (m, 2H), 3.64 - 3.52 (m, 1H), 3.50 - 3.25 (m, 2H), 2.81 (t, J=7.6Hz, 4H), 2.73 - 2.67 (m, 5H), 2.01 - 1.89 (m, 5H), 1.82 - 1.72 (m, 3H), 1.61 - 1.49 (m, 4H); MS (ESI): m/z (%) = 488.21 (100%) (M+H)+.
실시예-71
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(테트라히드로-2H-피란-4-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.33 (bs, 1H), 8.07 (s, 1H), 6.96 (s, 1H), 6.80 - 6.74 (m, 1H), 6.69 - 6.65 (m, 1H), 3.87 - 3.83 (m, 2H), 3.37 - 3.34 (m, 3H), 2.81 (t, J=7.6Hz, 4H), 2.67 (t, J=7.6Hz, 4H), 2.08 -1.94 (m, 4H), 1.65 - 1.62 (m, 2H), 1.55 - 1.30 (m, 2H); MS (ESI): m/z (%) = 391.15 (100%) (M+H)+.
실시예-72
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-니코티노일피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.35 (bs, 1H), 8.76 - 8.59 (m, 2H), 8.05 (s, 1H), 6.72 (d, J=8Hz, 0.72H), 7.77 (d, J=8Hz, 0.23H), 7.48 - 7.40 (m, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 6.57 - 6.55 (m, 1H), 4.86 - 4.50 (m, 1H), 3.65 - 3.59 (m, 1H), 3.41 - 3.37 (m, 1H), 2.78 (t, J=7.6Hz, 4H), 2.65 (t, J=7.6Hz, 4H), 2.20 - 2.13 (m, 1H), 1.96 - 1.84 (m, 7H); MS (ESI): m/z (%) = 481.18 (100%) (M+H)+.
실시예-73
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(테트라히드로퓨란-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.40 (bs, 1H), 8.11 (s, 1H), 6.96 (s, 1H), 6.81 (dd, J=4.0Hz, J=14.8Hz, 1H), 6.74 (dd, J=1.2Hz, J=15.2Hz, 1H), 4.57 - 4.53 (m, 1H), 3.86 - 3.81 (m, 1H), 3.76 - 3.70 (m, 1H), 2.81 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.16 - 2.07 (m, 1H), 2.01 - 1.94 (m, 4H), 1.90 - 1.79 (m, 2H), 1.67 - 1.62 (m, 1H); MS (ESI): m/z (%) = 377.15 (100%) (M+H)+.
실시예-74
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티오펜-2-일메틸)-피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.40 (bs, 1H), 8.10 (s, 1H), 7.43 - 7.39 (m, 1H), 7.01 - 6.86 (m, 4H), 6.71 - 6.63 (m, 1H), 3.93 (d, J=14Hz, 1H), 3.58 (d, J=14Hz, 1H), 3.28 - 3.24 (m, 1H), 2.97 - 2.92 (m, 1H), 2.77 (t, J=7.2Hz, 4H), 2.63 (t, J=7.2Hz, 4H), 2.33 - 2.04 (m, 1H), 2.04 - 1.88 (m, 5H), 1.75 - 1.68 (m, 2H), 1.59 - 1.54 (m, 1H); MS (ESI): m/z (%) = 472.12 (100%) (M+H)+.
실시예-75
tert-부틸(S,E)-2-(2-(N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO): δ = 10.06 (bs, 1H), 7.93 (s, 1H), 6.97 - 6.95 (m, 2H), 6.72 - 6.55 (m, 2H), 4.46 - 4.02 (m, 1H), 3.30 - 3.26 (m, 2H), 3.02 - 2.99 (m, 2H), 2.22 - 1.99 (m, 1H), 1.78 - 1.68 (m, 3H), 1.45 (s, 9H), 1.11 (d, J=6.8Hz, 12H); MS (ESI): m/z (%) = 398.29 (100%) (M-100)+; 520.36 (15%) (M+Na)+; 496.32 (100%) (M-H)+.
실시예-76
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO): δ = 9.40 (bs, 1H), 7.39 (bs, 1H), 7.02 - 6.76 (m, 3H), 6.39 - 6.22 (m, 1H), 4.05 - 4.04 (m, 1H), 3.17 - 3.13 (m, 4H), 2.06 - 1.56 (m, 5H), 1.10 - 1.09 (m, 12H); MS (ESI): m/z (%) = 398.26 (100%) (M-H)+.
실시예-77
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드.
1H NMR (400 MHz, DMSO-d6): δ = 10.90 (bs, 1H), 7.84 (bs, 1H), 6.94 (d, J=9.6Hz, 2H), 6.90 (d, J=15.2Hz, 1H), 6.58 - 6.53 (m, 1H), 3.08 - 2.95 (m, 4H), 2.33 - 2.27 (m, 1H), 2.23 (s, 3H), 2.07 - 1.97 (m, 1H), 1.78 - 1.73 (m, 2H), 1.59 - 1.50 (m, 1H), 6.75 (d, J=6.8Hz, 12H); MS (ESI): m/z (%) = 412.26 (100%) (M+H)+.
실시예-78
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소부틸-2-메틸-피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 8.03 (bs, 1H), 6.89 (s, 1H), 6.88 (d, J=15.6Hz, 1H), 6.54 (d, J=15.6Hz, 1H), 2.81 - 2.77 (m, 6H), 2.70 - 2.57 (m, 5H), 2.13 - 2.00 (m, 2H), 1.98 - 1.91 (m, 4H), 1.75 - 1.53 (m, 5H), 1.06 (s, 3H), 0.90 - 0.79 (m, 6H); MS (ESI): m/z (%) = 446.26 (100%) (M+H)+.
실시예-79
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-프로필피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 7.99 (bs, 1H), 6.90 (s, 1H), 6.67 (d, J=15.6Hz, 1H), 6.57 (d, J=16.0Hz, 1H), 2.93 - 2.87 (m, 1H), 2.79 (t, J=7.2Hz, 4H), 2.70 - 2.66 (m, 5H), 2.33 - 2.29 (m, 2H), 1.99 - 1.91 (m, 4H), 1.85 - 1.66 (m, 4H), 1.45 - 1.33 (m, 2H), 1.09 (s, 3H), 0.80 (t, J=7.6Hz, 3H); MS (ESI): m/z (%) = 432.25 (100%) (M+H)+.
실시예-80
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티아졸-2-일)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.4 (bs, 1H), 8.09 (s, 1H), 7.14 (d, J=3.6Hz, 1H), 6.96 (s, 1H), 6.84 - 6.79 (m, 1H), 6.75 (d, J=3.6Hz, 1H), 6.72 - 6.66 (m, 1H), 4.59 - 4.58 (m, 1H), 3.58 - 3.53 (m, 1H), 3.41 - 3.34 (m, 1H), 2.81 (t, J=7.2Hz, 4H), 2.64 (t, J=7.2Hz, 4H), 2.30 - 2.18 (m, 1H), 2.04 - 1.87 (m, 7H); MS (ESI): m/z (%) = 459.17 (100%) (M+H)+.
실시예-81
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-3-일)에텐-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.04 (brs, 1H), 7.57 (s, 1H), 6.81 (s, 1H), 6.67 (d, J = 15.2 Hz, 1H), 6.24 (dd, J = 15.2 Hz, J = 6.0 Hz, 1H), 3.23 - 3.12 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.51 - 2.49 (m, 2H), 1.97- 1.89 (m, 5H), 1.79 - 1.76 (m, 2H), 1.63 - 1.59 (m, 1H), 1.37 - 1.29 (m, 1H); MS (ESI): m/z (%) = 390.15 (100%) (M+H)+.
실시예-82
(E)-2-(1-에틸피페리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.82 (s, 1H), 6.94 (s, 1H), 6.70 (d, J = 15.2 Hz, 1H), 6.53 (dd, J = 15.2 Hz, J = 6.0 Hz, 1H), 2.98 - 2.89 (m, 2H), 2.79(t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.57 - 2.54 (m, 2H), 2.21- 2.09 (m, 2H), 1.99- 1.91 (m, 4H), 1.72 - 1.69 (m, 2H), 1.58 - 1.50 (m, 1H), 1.24 - 1.32 (m, 2H), 1.05(t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 418.18 (100%) (M+H)+.
실시예-83
(E)-tert-부틸3-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-피페리딘-1-카르복실레이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.4 (brs, 1H), 7.93 (s, 1H), 6.93 (s, 1H), 6.74 (d, J = 15.2 Hz, 1H), 6.61 (dd, J = 15.2 Hz, J = 6.8 Hz, 1H), 3.75 - 3.64(m, 2H), 2.93 - 2.88 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.38 - 2.33 (m, 1H), 2.00- 1.93 (m, 4H), 1.80- 1.70 (m, 1H), 1.59 - 1.55 (m, 1H), 1.39 (s, 9H), 1.36 - 1.34 (m, 1H), 0.91 - 0.81 (m, 1H); MS (ESI): m/z (%) = 390.16 (100%) [(M-100)+H]+, 488.17 (100%) (M-1).
실시예-84
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피페리딘-3-일)에텐설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.4 (brs, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.79 (d, J = 15.2 Hz, 1H), 6.66 (dd, J = 15.2 Hz, J = 6.4 Hz, 1H), 3.47 - 3.39 (m, 2H), 2.87 (s, 3H), 2.80 (t, J = 7.6 Hz, 4H), 2.68 (t, J = 7.6 Hz, 4H), 2.60 - 2.46 (m, 3H), 2.00- 1.91 (m, 4H), 1.80- 1.72 (m, 2H), 1.57 - 1.49 (m, 1H), 1.35 - 1.24 (m, 1H); MS (ESI): m/z (%) = 468.14 (100%) (M+H)+, 490.40 (50%) (M+Na), 466.11 (100%) (M-1).
실시예-85
(E)-2-(1-아세틸피페리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.00 (s, 1H), 6.94 (s, 1H), 6.80 - 6.65 (m, 2H), 4.16 - 4.10 (m, 1H), 3.77 - 3.63 (m, 1H), 3.09 - 2.93 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 - 2.64 (m, 5H), 2.39 - 2.26 (m, 1H), 2.00- 1.91 (m, 7H), 1.90- 1.77 (m, 1H), 1.74 - 1.57 (m, 1H), 1.54 - 1.28 (m, 2H); MS (ESI): m/z (%) = 468.14 (100%) (M+H)+, 490.40 (50%) (M+Na), 466.11 (100%) (M-1).
실시예-86
tert-부틸(E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-아제티딘-1-카르복실레이트
실시예 86은 중간체-11을 사용하여 중간체-3a의 합성에 대해 설명된 절차에 따라 제조하였다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.57 (brs, 1H), 7.83 (s, 1H), 6.89 (s, 1H), 6.73 (d, J = 15.2 Hz, 1H), 6.66 (dd, J = 15.2 Hz, J = 4.4 Hz, 1H), 4.73 - 4.84 (m, 1H), 3.80 - 3.70 (m, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.46 - 2.33 (m, 1H), 2.04 - 1.97 (m, 5H), 1.35 (s, 9H); MS (ESI): m/z (%) = 484.84 (90%) (M+H)+ , 460.23 (100%) (M-1).
실시예-87
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸아제티딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.45 (brs,1H), 7.98 (s, 1H), 6.92 (s, 1H), 6.84 (d, J = 14.8 Hz, 1H), 6.72 (dd, J = 15.2 Hz, J = 5.2 Hz 1H), 3.95 - 3.82 (m, 1H), 3.44 - 3.36 (m, 2H), 3.09 - 2.95 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 6.8 Hz, 4H), 2.30 (s, 3H), 2.26 - 2.20 (m, 1H), 2.03 - 1.89 (m, 4H); MS (ESI): m/z (%) = 376.19 (100%) (M+H)+, 374.16 (100%) (M-1).
실시예-88
(E)-2-(아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.51 (s, 1H), 6.94 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.55 (dd, J = 15.2 Hz, J = 7.2 Hz, 1H), 5.01 - 4.95 (m, 1H), 3.89 - 3.82 (m, 1H), 3.72 - 3.62 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 6.8 Hz, 4H), 2.50 - 2.33 (m, 1H), 1.96 - 1.88 (m, 5H); MS (ESI): m/z (%) = 362.24 (100%) (M+H)+.
실시예-89
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.36 (brs, 1H), 7.99 (s, 1H), 6.94 - 6.90 (m, 2H), 6.77 (dd, J = 14.8 Hz, J = 5.2 Hz, 1H), 3.99 - 3.86 (m, 1H), 3.46 - 3.39 (m, 2H), 3.13 - 2.96 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 2.51 - 2.33 (m, 1H), 2.30 - 2.16 (m, 1H), 1.99 - 1.92 (m, 5H), 0.82 - 0.61 (m, 1H), 0.50 - 0.30 (m, 2H), 0.22 - 0.08 (m, 2H); MS (ESI): m/z (%) = 416.29 (100%) (M+H)+.
실시예-90
(S,E)-2-(1-((5-클로로티오펜-2-일)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.01 (s, 1H), 7.68 (t, J = 1.2 Hz, 1H),7.36 (d, J = 4.0 Hz, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.82 (s, 1H), 4.40 (d, J = 5.2 Hz, 1H), 3.43 (t, J = 6.8 Hz, 1H), 3.32 (s,1H), 3.20 (d, J = 7.6 Hz, 1H) , 2.80 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 8.8 Hz, 4H), 1.95 (m,4H), 1.74 (m, 3H), 1.64 (s, 1H); MS (ESI): m/z (%) = 556 (100%) (M+1).
실시예-91
(S,E)-2-(1-(벤질설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.86 (s, 1H), 7.42 (m, 2H), 7.34 (t, J = 4.0 Hz, 3H), 6.87 (s, 1H), 6.71 (s, 1H), 6.45 (m, 1H), 4.46 (s,2H), 4.37(d, J = 8.0 Hz, 1H), 3.22 (s, 1H), 2.78 (t, J = 7.6 Hz, 4H) , 2.66 (t, J = 7.2 Hz, 4H), 1.99 (m,1H), 1.95 (m, 4H), 1.74 (m, 3H); MS (ESI): m/z (%) = 530 (100%) (M+1).
실시예-92
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-((4-메톡시페닐)설포닐) 피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.93 (s, 1H), 7.79 (d, J = 2.8 Hz, 2H), 7.12 (d, J = 2.0 Hz, 2H), 6.90 (s, 1H), 6.85 (s, 1H), 6.66 (s, 1H), 6.60 (d, J = 5.6 Hz, 1H), 6.57 (d, J = 4.4 Hz, 1H), 4.4 (m,1H), 3.84 (s, 3H), 3.22 (m, 1H), 2.78(t, J = 7.2 Hz, 4H) , 2.70 (t, J = 7.2 Hz, 4H), 1.99 (m, 4H), 1.68 (m, 3H), 1.60 (m, 1H); MS (ESI): m/z (%) = 546 (100%) (M+1).
실시예-93
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-((4-플루오로페닐)설포닐) 피롤리딘-2-일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.02 (s, 1H), 7.94 (d, J = 2.0 Hz, 2H), 7.47 (d, J = 3.6 Hz, 2H), 6.90 (s, 1H), 6.87 (s, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.41 (m,1H), 3.36 (m, 1H), 2.78(t, J = 7.2 Hz, 4H) , 2.69 (t, J = 7.2 Hz, 4H), 1.99 (m, 4H), 1.68 (m, 3H), 1.60 (m, 1H); MS (ESI): m/z (%) = 534 (100%) (M+1).
실시예-94
(S,E)-2-(1-((2-시아노페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.11 (d, J = 1.2 Hz, 2H), 7.90 (d, J = 1.2 Hz, 2H), 7.83 (s, 1H), 6.82 (s, 1H), 6.70 (d, J = 14.8 Hz, 1H), 6.30 (s, 1H), 4.51 (s,1H), 3.32 (s, 2H), 2.77(t, J = 7.2 Hz, 4H) , 2.70 (t, J = 7.2 Hz, 4H), 1.92 (m, 4H), 1.80 (m, 2H), 1.74 (m, 2H); MS (ESI): m/z (%) = 541.14 (100%) (M+1).
실시예-95
(S,E)-2-(1-(시클로헥실설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.78 (s, 1H), 6.85 (s, 1H), 6.70 (d, J = 14.8 Hz, 1H), 6.41 (s, 1H), 4.46 (s,1H), 3.42 (m, 1H), 3.08 (s, 1H), 2.78(t, J = 7.6 Hz, 4H) , 2.70 (t, J = 7.2 Hz, 4H), 2.09 (d, J = 4.8 Hz, 1H )1.94 (m, 7H), 1.83 (m, 3H), 1.72 (m, 1H), 1.52 (s, 1H), 1.32 (m, 3H), 1.24 (s, 2H), 1.08 (s, 1H); MS (ESI): m/z (%) = 522.19 (100%) (M+1).
실시예-96
(S,E)-2-(1-(4-플루오로벤질)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.03 (s, 1H), 7.28 (t, J = 6.0 Hz, 2H), 7.06 (t, J = 8.8 Hz, 2H), 6.89 (s, 1H), 6.86 (s, 1H), 6.62 (m, 1H), 3.81 (d, J = 13.2 Hz, 2H), 3.16 (m,2H), 2.68 (t, J = 5.6 Hz, 4H) , 2.62 (t, J = 7.2 Hz, 4H), 2.16 (m, 1H), 1.90 (m,1H), 1.85 (m, 4H), 1.70 (m, 2H), 1.55 (m,. 1H); MS (ESI): m/z (%) = 484.19 (100%) (M+1).
실시예-97
(S,E)-2-(1-((4-시아노페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.06 (d, J = 8.4 Hz, 2H), 8.01 (t, J = 8.6 Hz, 2H), 7.86 (s, 1H), 6.87 (s, 1H), 6.80 (d, J = 14.8 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 5.6 Hz, 1H ), 3.36 (m,2H), 3.18 (m, 1H), 2.78 (t, J = 7.2 Hz, 4H) , 2.70 (t, J = 7.2 Hz, 4H), 1.92 (m, 4H), 1.67 (m,3H), 1.56 (m, 1H); MS (ESI): m/z (%) = 541.15 (100%) (M+1).
실시예-98
(S,E)-2-(1-(4-시아노벤질)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.01 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 6.0 Hz, 1H), 6.91 (s, 1H), 6.65 (m, 1H), 3.86 (d, J = 13.6 Hz, 2H), 3.25 (m, 1H) , 2.79 (m, 5H), 2.61 (m, 4H), 2.22 (m, 1H), 2.12 (m, 1H), 1.98 (m, 4H), 1.72 (m, 2H), 1. 76 (m, 1H); MS (ESI): m/z (%) = 491.15 (100%) (M+1).
실시예-99
(S,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.90 (s, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 6.98 (d, J1 = 0.8 Hz, 1H), 6.98 (t, J2= 1.2 Hz, 1H), 6.38 (m, 1H), 4.08 (m, 1H ), 3.22 (m,2H), 2.70 (m, 8H), 2.15 (m, 1H), 1.98 (m, 6H), 1.71 (m,1H), 1.56 (m, 1H); MS (ESI): m/z (%) = 372.87 (100%) (M-1).
실시예-100
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.41 (s, 1H), 6.86 (d, J = 15.6 Hz, 1H), 6.79 (s, 1H), 6.28 (d, J =6.0 Hz, 1H), 3.61 (s,2H), 3.14 (d, J = 12.8 Hz, 1H), 2.81 (t, J = 7.2 Hz, 4H) , 2.70 (t, J = 7.2 Hz, 4H), 1.98 (m, 5H), 1.81 (m,2H), 1.69 (m, 1H), 1.48 (m, 3H); MS (ESI): m/z (%) = 390.13 (100%) (M+1).
실시예-101
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피페리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.92 (s, 1H), 6.89 (s, 1H), 6.80 (d, J = 14.8 Hz, 1H), 6.42 (d, J= 8.4 Hz, 1H), 2.92 (t, J = 5.2 Hz, 2H), 2.82 (t, J = 7.2 Hz, 4H) , 2.72 (t, J = 7.2 Hz, 4H), 2.27 (m, 4H), 1.92 (m, 5H), 1.62 (m, 3H), 1.44 (s, 2H); MS (ESI): m/z (%) = 404.15 (100%) (M+1).
실시예-102
(E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ =7.83 (s, 1H), 7.44 (s, 1H), 6.88 (d, J = 14.8 Hz, 1H), 6.53 (d, J= 8.0 Hz, 1H), 3.13 (s, 3H), 2.82 (t, J = 7.2 Hz, 4H) , 2.72 (t, J = 7.2 Hz, 4H) , 2.39 (s, 2H), 2.33 (d, J = 2.0 Hz, 3H), 2.11 (m, 5H), 1.81 (m, 2H), 1.78 (m, 1H); MS (ESI): m/z (%) = 390.14 (100%) (M+1).
실시예-103
(E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.87 (s, 1H), 7.45 (s, 1H), 6.77 (d, J = 14.8 Hz, 1H), 6.68 (d, J= 4.8 Hz, 1H), 4.48 (t, J = 4.0 Hz, 1H), 2.99 (s, 3H), 2.82 (t, J = 7.2 Hz, 4H) , 2.72 (t, J = 7.2 Hz, 4H) , 2.11 (m, 5H), 1.81 (m, 3H); MS (ESI): m/z (%) = 454.09 (100%) (M+1).
실시예-104
((E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-3-(피페리딘-2-일)프로프-1-엔-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.44 (s, 1H), 6.79 (s, 1H), 6.47 (d, J = 15.2 Hz, 1H), 6.20 (m,1H), 2.85 (t, J = 7.2 Hz, 5H), 2.70 (t, J = 7.2 Hz, 4H) , 2.33 (t, J = 1.6 Hz, 2H) , 1.98 (m, 6H), 1.73 (m, 3H), 1.61 (s, 1H), 1.38 (m, 2H). 1.24 (s, 1H); MS (ESI): m/z (%) = 404.20 (100%) (M+1).
실시예-105
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.52 (s, 1H), 6.88 (d, J = 15.6 Hz, 1H), 6.81 (s, 1H), 6.46 (d, J = 15.6 Hz, 1H), 3.21 (m, 2H ), 3.12 (m,1H), 2.75 (t, J = 7.2 Hz, 4H ), 2.69 (t, J = 7.2 Hz, 4H ), 1.98 (m, 7H), 1.78 (s,2H), 1.38 (s, 3H); MS (ESI): m/z (%) = 390.24 (100%) (M+1).
실시예-106
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ =8.04 (s, 1H), 6.93 (s, 1H), 6.73 (d, J = 15.2 Hz, 1H), 6.65 (d, J= 15.2 Hz, 1H), 2.80 (t, J = 7.2 Hz, 4H) , 2.68 (t, J = 7.2 Hz, 4H) , 2.20 (s, 3H), 1.96 (m, 4H), 1.72 (m, 4H), 1.13 (s, 3H); MS (ESI): m/z (%) = 404.25 (100%) (M+1).
대안적으로, 실시예 106은 또한 유기 합성 분야의 당업자에게 공지된 통상적인 기술과 함께, 중간체 9 및 (S)-1,2-디메틸피롤리딘-2-카브알데히드를 사용하여 중간체-7b (실시예 111)의 합성에 대해 기재된 절차에 따라 제조하였다.
실시예-107
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(인돌린-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =7.89 (s, 1H), 7.04 (d, J=3.2 Hz, 1H), 6.99 (d, J=6.8 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.62 (d, J =13.8 Hz, 1H), 6.51 (d, J= 7.6 Hz, 2H), 5.95 (s, 1H), 4.4 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H), 1.95 (m, 1H ); MS (ESI): m/z (%) = 424.20 (100%) (M+1).
실시예-108
tert-부틸(E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)인돌린-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ =8.11 (s, 1H), 7.71 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.99 (d, J1= 0.8 Hz, 1H), 6.97 (d, J2= 0.8 Hz, 1H), 6.95 (s, 1H), 6.78 (d, J= 6.0 Hz, 1H), 6.66 (d, J= 15.6 Hz, 1H), 5.10 (m, 1H), 5.12 (m, 1H), 3.50 (m, 1H), 2.80 (t, J = 7.2 Hz, 5H) , 2.62 (t, J = 7.2 Hz, 4H) , 1.96 (m, 5H), 1.45 (s, 10H); MS (ESI): m/z (%) = 522.20 (100%) (M-1).
실시예-109
((S,E)-2-(1-(시클로프로필메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ =7.42 (s, 1H), 6.78 (s, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.21 (d, J= 15.2 Hz, 1H), 2.93 (t, J = 6.4 Hz, 1H) , 2.76 (t, J = 7.2 Hz, 4H) , 2.69 (t, J = 7.2 Hz, 4H), 2.33 (t, J = 1.62 Hz, 1H), 2.27 (t, J = 6.8 Hz, 1H), 2.01 (m, 1H), 1.93 (m, 4H), 1.76 (d, J = 5.62 Hz, 1H), 1.68 (d, J = 8.0 Hz, 1H), 1.60 (d, J = 4.4 Hz, 1H), 1.0 (s, 2H), 0.38 (t, J = 7.6 Hz, 2H); MS (ESI): m/z (%) = 444.26 (100%) (M+1).
실시예-110
(S,E)-2-(1-(시클로프로필설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ =8.05 (s, 1H), 6.94 (s, 1H), 6.81 (d, J = 0.8 Hz, 1H), 6.77 (d, J= 1.2 Hz, 1H), 6.68 (d, J = 15.2 Hz, 1H), 4.57 (m, 1H), 3.43 (m, 1H), 2.80 (t, J = 7.2 Hz, 1H) , 2.68 (t, J = 7.2 Hz, 4H), 1.99 (m, 5H), 1.81 (m, 2H), 0.95 (d, J = 6.4 Hz, 4H); MS (ESI): m/z (%) = 480.20 (100%) (M+1).
실시예-111
tert-부틸(S,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ =7.97 (s, 1H), 6.91 (s, 1H), 6.72 (d, J = 15.2 Hz, 1H), 6.54 (d, J= 7.68 Hz, 1H), 2.80 (t, J = 7.2 Hz, 4H) , 2.68 (t, J = 7.2 Hz, 5H) , 1.97 (m, 4H), 1.89 (s, 3H), 1.80 (m, 4H), 1.48 (s, 2H0, 1.44 (s, 2H), 1.38 (s, 10H); MS (ESI): m/z (%) = 488.24 (100%) (M-1).
실시예-112
tert-부틸(R,E)-2-(2-(N-((2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.55 (s, 1H), 7.89 (d, J = 16.0 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.89 - 6.79 (m, 1H), 6.56 - 6.49 (m, 1H), 3.39 - 3.35 (m, 2H), 3.05 - 3.00 (m, 2H), 1.93 - 1.90 (m, 1H), 1.83 - 1.77 (m, 2H), 1.69 - 1.64 (m, 1H), 1.44 (s, 3H), 1.37 (s, 9H), 1.13 (d, J = 6.8 Hz, 12H); MS (ESI): m/z (%) = 492.24 (100%) (M-1)-.
실시예-113
(R,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 11.10 (bs, 1H), 9.08 (bs, 2H), 8.24 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.11 (d, J = 15.6 Hz, 1H), 7.05 (d, J = 15.2 Hz, 1H), 3.33 - 3.29 (m, 2H), 3.07 - 3.00 (m, 2H), 2.13 - 1.83 (m, 4H), 1.46 (s, 3H), 1.12 (d, J = 6.8 Hz, 12H); MS (ESI): m/z (%) = 392.22 (100%) (M-TFA)+;
실시예-114
(R,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1,2-디메틸피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (bs, 1H), 7.83 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 15.2 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 3.33 - 3.22 (m, 2H), 2.83 - 2.80 (m, 1H), 2.73 - 2.67 (m, 1H), 2.15 (s, 3H), 1.80 - 1.69 (m, 4H), 1.18 - 1.10 (m, 15H); MS (ESI): m/z (%) = 408.23 (100%) (M+H)+.
실시예-115
(S,E)-2-(1-에틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (bs, 1H), 8.05 (bs, 1H), 6.93 (s, 1H), 6.74 (d, J = 15.2 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 2.96 - 2.89 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.6 Hz, 6H), 1.96 (quin, J = 7.2 Hz, 4H), 1.79 - 1.72 (m, 4H), 1.14 (s, 3H), 1.02 (t, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.16 (100%) (M+H)+.
실시예-116
비스소듐 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 6.76 (s, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.20 (d, J = 15.6 Hz, 1H), 2.75 (t, J = 7.6 Hz, 5H), 2.69 (t, J = 7.2 Hz, 4H), 2.64 - 2.59 (m, 1H), 2.08 (s, 3H), 1.90 (quin, J = 7.2 Hz, 4H), 1.74 - 1.68 (m, 3H), 1.62 - 1.61 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.17 (100%) (M-2Na)+.
실시예-117
소듐(R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.36 (s, 1H), 6.77 (s, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.19 (d, J = 15.6 Hz, 1H), 2.76 (t, J = 7.2 Hz, 5H), 2.69 (t, J = 7.2 Hz, 4H), 2.64 - 2.59 (m, 1H), 2.08 (s, 3H), 1.91 (quin, J = 7.6 Hz, 4H), 1.74 - 1.68 (m, 3H), 1.62 - 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.17 (100%) (M-Na)+.
실시예-118
tert-부틸(S,E)-2-(2-(N-((2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.55 (s, 1H), 7.89 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.84 (d, J = 15.6 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 3.37 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 1.91 - 1.90 (m, 1H), 1.83 - 1.77 (m, 2H), 1.69 - 1.64 (m, 1H), 1.44 (s, 3H), 1.37 (s, 9H), 1.13 (d, J = 6.8 Hz, 12H); MS (ESI): m/z (%) = 494.31 (10%) (M+1)+.
실시예-119
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 11.10 (bs, 1H), 9.10 (bs, 2H), 8.28 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 15.6 Hz, 1H), 7.00 (d, J = 15.2 Hz, 1H), 3.35 - 3.30 (m, 1H), 3.24 - 3.20 (m, 1H), 3.07 - 3.00 (m, 2H), 2.10 - 1.98 (m, 2H), 1.93 - 1.85 (m, 2H), 1.46 (s, 3H), 1.12 (d, J = 6.8 Hz, 12H); MS (ESI): m/z (%) = 394.27 (100%) (M-TFA)+.
실시예-120
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1,2-디메틸피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.10 (bs, 1H), 7.92 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 6.68 (d, J = 14.8 Hz, 1H), 6.61 (d, J = 15.6 Hz, 1H), 3.07 - 3.02 (m, 2H), 2.85 - 2.83 (m, 1H), 2.69 - 2.67 (m, 1H), 2.14 (s, 3H), 1.82 - 1.66 (m, 4H), 1.12 - 1.07 (m, 15H); MS (ESI): m/z (%) = 408.23 (100%) (M+H)+.
실시예-121
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(옥세탄-3-일)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.39 (bs, 1H), 8.14 (s, 1H), 6.95 (s, 1H), 6.71 - 6.59 (m, 2H), 4.65 (t, J=6.4Hz, 1H), 4.55 (t, J=6.8Hz, 1H), 4.45 - 4.39 (m, 2H), 4.05 - 3.98 (m, 1H), 3.13 - 3.07 (m, 1H), 3.02 - 2.99 (m, 1H), 2.81 (t, J=7.2Hz, 4H), 2.69 (t, J=7.2Hz, 4H), 2.01 - 1.63 (m, 8H), 1.03 (s, 3H); MS (ESI): m/z (%) = 446.24 (100%) (M+H)+.
실시예-122
tert-부틸 (S,E)-2-(2-(N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d6): δ = 10.61 (bs, 1H), 7.89 - 7.85 (m, 1H), 6.97 (d, J=10Hz, 2H), 6.90 - 6.79 (m, 1H), 6.55 - 6.49 (m, 1H), 3.38 - 3.35 (m, 2H), 3.03 - 3.01 (m, 2H), 1.92 - 1.64 (m, 3H), 1.47 - 1.43 (m, 3H), 1.36 (s, 9H), 1.11 (d, J=7.2Hz, 12H); MS (ESI): m/z (%) = 512.30 (8%) (M+H)+, 534.29 (8%) (M+Na)+.
실시예-123
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트
1H NMR (400 MHz, DMSO-d6): δ = 11.11 (bs, 1H), 9.08 (bs, 2H), 8.25 (s, 1H), 7.09 (d, J=15.6Hz, 1H); 7.00 - 6.95 (m, 3H), 3.42 - 3.40 (m, 1H), 3.21 - 3.17 (m, 1H), 3.06 - 2.99 (m, 2H), 2.10 - 1.83 (m, 4H), 1.45 (s, 3H), 1.11 (d, J=5.6Hz, 12H); MS (ESI): m/z (%) = 412.23 (100%) (M+H)+;
실시예-124
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 7.87 (s, 1H), 6.93 (d, J=10Hz, 2H); 6.66 - 6.92 (m, 2H), 3.10 - 3.04 (m, 2H), 2.83 - 2.67 (m, 2H), 2.15 (s, 3H), 1.76 - 1.69 (m, 4H), 1.11 - 1.09 (m, 15H); MS (ESI): m/z (%) = 426.29 (100%) (M+H)+;
실시예-125
(E)-2-(1-아세틸아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.40 (br s, 1H), 8.15 - 8.09 (m, 1H), 6.96 - 6.71 (m, 3H), 5.14 - 4.87 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.77 - 2.64 (m, 4H), 2.60 - 2.56 (m, 1H), 2.01 - 1.94 (m, 5H), 1.78 (s, 2H), 1.66 (s, 1H); MS (ESI): m/z (%) = 404.11 (100%) (M+H)+.
실시예-126
tert-부틸(R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)에틸)(메틸)카바메이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.38 (brs, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.80 (d, J = 14.4 Hz, 1H), 6.63 (dd, J = 14.8 Hz J = 6.8 Hz, 1H), 3.23 - 3.07 (m, 4H), 2.81 (t, J = 7.2 Hz, 4H), 2.72 - 2.58 (m, 8H), 2.33 - 2.18 (m, 2H), 2.03 - 1.91 (m, 5H), 1.83 - 1.62 (m, 2H), 1.55 - 1.46 (m, 1H), 1.37 (s, 9H); MS (ESI): m/z (%) = 533.21 (100%) (M+H)+.
실시예-127
(S,E)-2-(1-알릴피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.07 (s, 1H), 6.95 (s, 1H), 6.84 (d, J = 15.2 Hz, 1H), 6.64 (dd, J = 15.2 Hz, J = 7.2 Hz, 1H), 5.85 - 5.80 (m, 1H), 5.19 - 5.14 (m, 1H), 5.09 - 5.07 (m, 1H), 3.28 - 3.27 (m, 1H), 3.21 - 3.15 (m, 1H), 3.05 - 3.01 (m, 1H), 2.86 - 2.78 (m, 4H), 2.73 - 2.64 (m, 4H), 2.60 - 2.56 (m, 1H), 2.30 - 2.23 (m, 1H), 2.07 - 1.97 (m, 5H), 1.80 - 1.70 (m, 2H), 1.59 - 1.50 (m, 1H); MS (ESI): m/z (%) = 416.14 (100%) (M+H)+.
실시예-128
(S,E)-2-(1-(1H-벤조[d]이미다졸-6-카르보닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 12.65 (brs, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.85 - 7.69 (m, 1H), 7.67 - 7.50 (m, 1H), 7.49 - 7.23 (m, 1H), 6.92 (s, 1H), 6.91 - 6.53 (m, 2H), 4.98 - 4.68 (m, 1H), 3.72 - 3.53 (m, 1H), 3.50 - 3.42 (m, 1H), 2.86 - 2.72 (m, 4H), 2.66 (t, J = 6.8 Hz, 4H), 2.29 - 2.12 (m, 1H), 1.98 - 1.77 (m, 7H); MS (ESI): m/z (%) = 520.24 (90%) (M+H)+.
실시예-129
(S,E)-2-(1-(시클로프로필설포닐)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.01 (s, 1H), 6.94 (s, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.71 (dd, J = 14.8 Hz, J = 6.4 Hz, 1H), 3.46 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.63 - 2.56 (m, 2H), 2.07 - 1.91 (m, 6H), 1.90 - 1.74 (m, 1H), 1.57 (s, 3H), 0.97 - 0.89 (m, 4H); MS (ESI): m/z (%) = 494.22 (100%) (M+H)+.
실시예-130
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(4-메톡시벤질)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ =8.01 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 6.0 Hz, 1H), 6.91 (s, 1H), 6.65 (m, 1H), 3.86 (d, J = 13.6 Hz, 2H), 3.25 (m, 1H) , 2.80 (t, J = 7.2 Hz, 1H) , 2.68 (t, J = 7.2 Hz, 4H), 2.12 (m, 1H), 1.98 (m, 4H), 1.72 (m, 2H), 1. 76 (m, 1H); MS (ESI): m/z (%) = 496.33 (100%) (M+1).
실시예-131
tert-부틸 5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)헥사히드로시클로펜타[c]피롤-2(1H)-카르복실레이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.34 (brs, 1H), 8.03 (s, 1H), 6.94 (s, 1H), 6.84 (d, J = 14.8 Hz, 1H), 6.66 (dd, J = 14.8 Hz, J = 7.6 Hz, 1H), 3.48 - 3.35 (m, 1H), 3.14 - 3.07 (m, 2H), 3.99 - 2.88 (m, 2H), 2.81 (t, J = 6.8 Hz, 4H), 2.69 - 2.66 (m, 5H), 2.47 - 2.39 (m, 3H), 2.01 - 1.91 (m, 7H), 1.81- 1.69 (m, 2H), 1.66 - 1.50 (m, 2H), 1.38 (s, 9H), 1.31 - 1.08 (m, 2H); MS (ESI): m/z (%) = 585.29 (100%) (M+H)+.
실시예-132
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-((2R)-1-(옥타히드로시클로-펜타[c]피롤-5-일)피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.54 (brs, 1H), 9.08 (s, 1H), 8.57 (s, 2H), 7.24 - 7.22 (m, 1H), 6.97 (s, 1H), 6.91 - 6.81(m, 1H), 4.50 - 4.28 (m, 1H), 3.63 - 3.45 (m, 2H), 3.39 - 3.16 (m, 2H), 3.17 - 2.93 (m, 2H), 2.82 (t, J = 7.2 Hz, 4H), 2.77 - 2.64 (m, 5H), 2.38 - 2.09 (m, 3H), 2.01 - 1.91 (m, 6H), 1.90- 1.78 (m, 1H), 1.62 - 1.39 (m, 2H), 1.05 - 1.03 (m, 2H); MS (ESI): m/z (%) = 485.25 (100%) (M+H)+.
실시예-133
(E)-2-(1-(시클로프로필설포닐)아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.54 (brs, 1H), 8.12 (s, 1H), 6.97 - 6.93 (m, 2H),6.86 (dd, J = 15.2 Hz, J = 4.8 Hz, 1H), 5.08 - 5.02 (m, 1H), 4.05 - 3.99 (m, 1H), 3.66 - 3.61 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.78 - 2.73 (m, 1H), 2.68 (t, J = 7.2 Hz, 4H), 2.46 - 2.43 (m, 1H), 2.15 - 2.10 (m, 1H), 2.01- 1.94 (m, 4H), 1.05 - 0.98 (m, 2H), 0.94 - 0.90 (m, 2H); MS (ESI): m/z (%) = 466.08 (100%) (M+H)+.
실시예-134
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-(티아졸-2-일)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ = 10.59 (bs, 1H), 7.92 (s, 1H), 7.28 - 7.25 (m, 1H), 7.16 - 7.13 (m, 3H), 6.85 - 6.76 (m, 2H), 6.66 (d, J=15.2Hz, 1H), 4.57 - 4.55 (m, 1H), 3.51 - 3.50 (m, 1H), 3.39 - 3.37 (m, 1H), 3.05 - 2.98 (m, 2H), 2.23 - 2.19 (m, 1H), 1.99 - 1.83 (m, 3H), 1.11 (d, J=6.8Hz, 12H); MS (ESI): m/z (%) = 463.16 (100%) (M+H)+.
실시예-135
tert-부틸(S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-일)에틸)(메틸)카바메이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.37 (bs, 1H), 8.06 (s, 1H), 6.95 (s, 1H), 6.72 (d, J = 15.6 Hz, 1H), 6.66 (d, J = 15.6 Hz, 1H), 3.2 - 3.17 (m, 1H), 2.81 (t, J = 6.8 Hz, 4H), 2.68 - 2.65 (m, 8H), 2.43 - 2.42 (m, 1H), 1.96 (quin, J = 7.2 Hz, 4H), 1.75 - 1.65 (m, 4H), 1.41 - 1.37 (m, 12H), 1.1 (s, 3H); MS (ESI): m/z (%) = 547.32 (100%) (M+H)+.
실시예-136
포타슘 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.33 (s, 1H), 6.77 (s, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 2.77 - 2.72 (m, 5H), 2.69 (t, J = 7.2 Hz, 4H), 2.64 - 2.58 (m, 1H), 2.08 (s, 3H), 1.90 (quin, J = 7.6 Hz, 4H), 1.75 - 1.70 (m, 3H), 1.62 - 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.21 (100%) (M-K)+.
실시예-137
tert-부틸(E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)아제티딘-1-일)에틸)(메틸)카바메이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.03 (s, 1H), 6.94 (m, 1H), 6.85 - 6.64 (m, 2H), 3.88 - 3.72 (m, 1H), 2.96 - 2.88 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 - 2.71 (m, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.61 - 2.54 (m, 1H), 2.46 - 2.40 (m, 1H), 2.25 - 2.19 (m, 1H), 1.99 - 1.92 (m, 2H), 1.41 - 1.38 (m, 12H); MS (ESI): m/z (%) = 519.26 (90%) (M+H)+, 517.20 (90%) (M-1).
실시예-138
(S,E)-2-(1-(시클로헥실메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.36 (brs, 1H), 8.04 (s, 1H), 6.95 (m, 1H), 6.78 - 6.62 (m, 2H), 2.81(t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), ), 2.65 - 2.55 (m, 1H), 2.26 - 2.02 (m, 2H), 2.00- 1.91 (m, 5H), 1.86 - 1.71 (m, 4H), 1.70 - 1.50 (m, 5H), 1.43 - 1.24 (m, 1H), 1.23 - 1.13 (m, 2H), 1.12 - 1.00 (m, 4H), 0.86 - 0.67 (m, 2H); MS (TOF): m/z (%) = 486.2891 (100%) (M+H)+, 484.2571 (100%) (M-1).
실시예-139
소듐(R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-(테트라히드로-2H-티오피란-4-일)피롤리딘-2-일)비닐)설포닐)아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.31 (s, 1H), 6.76 (s, 1H), 6.63 (d, J = 15.2 Hz, 1H), 6.06 (dd, J = 15.2 Hz, J = 7.6 Hz, 1H), 3.43 - 3.36 (m, 1H), 2.87 - 2.64 (m, 10H), 2.65 - 2.42 (m, 5H), 2.03 - 1.84 (m, 7H), 1.68 - 1.43 (m, 5H); MS (ESI): m/z (%) = 476.25 (100%) (M+H)+, 474.20 (100%) (M-1).
실시예-140
소듐(R,E)-((2-(1-시클로헥실피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.33 (s, 1H), 6.77 (s, 1H), 6.63 (d, J = 15.2 Hz, 1H), 6.09 (dd, J = 15.2 Hz, J = 7.6 Hz, 1H), 3.34 - 3.42 (m, 1H), 2.84 - 2.79 (m, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.41 - 2.31 (m, 1H), 1.94 - 1.80 (m, 5H), 1.75 - 1.61 (m, 7H), 1.54 - 1.41 (m, 2H), 1.24 - 1.07 (m, 5H); MS (TOF): m/z (%) = 458.2811 (100%) (M+H)+.
실시예-141
소듐(S,E)-((2,6-디이소프로필페닐)카르바모일)((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.24 (s, 1H), 7.11 (t, J = 8.4 Hz, 1H), 7.04 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.21 (d, J = 16.0 Hz, 1H), 3.23 - 3.16 (m, 2H), 2.74 - 2.67 (m, 1H), 2.65 - 2.59 (m, 1H), 2.08 (s, 3H), 1.75 - 1.71 (m, 3H), 1.61 - 1.59 (m, 1H), 1.1 (d, J = 6.4 Hz, 12H), 1.0 (s, 3H); MS (ESI): m/z (%) = 408.25 (100%) (M-Na)+.
실시예-142
소듐(R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-메틸피롤리딘-2-일)비닐)설포닐)아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.37 (s, 1H), 6.77 (s, 1H), 6.64 (d, J = 15.2 Hz, 1H), 6.07 (d, J = 15.2 Hz, 1H), 3.0 - 2.95 (m, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.59 - 2.53 (m, 1H), 2.14 (s, 3H), 2.13 - 2.06 (m, 2H), 1.91 (quin, J = 7.2 Hz, 4H), 1.73 - 1.60 (m, 3H), 1.54 - 1.49 (m, 1H); MS (ESI): m/z (%) = 390.20 (100%) (M-Na)+.
실시예-143
포타슘(R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-메틸피롤리딘-2-일)비닐)설포닐)아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.31 (s, 1H), 6.76 (s, 1H), 6.67 (d, J = 15.2 Hz, 1H), 6.03 - 6.01 (m, 1H), 2.97 (bs, 1H), 2.76 (bs, 4H), 2.69 (bs, 4H), 2.14 - 2.08 (m, 4H), 1.91 (bs, 5H), 1.68 (bs, 3H), 1.49 (bs, 1H); MS (ESI): m/z (%) = 390.20 (100%) (M-K)+.
실시예-144
소듐(S,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드
1H NMR (400 MHz, DMSO-d6): δ =7.33 (s, 1H), 6.77 (s, 1H), 6.56 (d, J = 15.2 Hz, 1H), 6.16 (d, J= 16 Hz, 1H), 2.76 (t, J = 7.2 Hz, 4H) , 2.69 (t, J = 7.2 Hz, 4H) , 2.62 (m, 1H), 2.08 (s, 3H), 1.90 (m, 4H), 1.72 (m, 4H), 1.60 (m, 3H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+1).
실시예-145
소듐(S,E)-((2-(1-에틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드
1H NMR (400 MHz, DMSO-d6): δ = 7.36 (s, 1H), 6.77 (s, 1H), 6.61 (d, J=15.2Hz, 1H); 6.05 (dd, J=8.0Hz, J=15.2Hz, 1H); 3.10 - 3.05 (m, 1H), 2.78 - 2.65 (m, 10H), 2.12 - 1.85 (m, 7H), 1.71 - 1.66 (m, 2H), 1.49 - 1.44 (m, 1H), 0.98 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 426.20 (50%) (M+H)+.
실시예-146
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-히드록시에틸)피롤리딘-2-일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ =7.90 (s, 1H), 6.90 (s, 1H), 6.84 (d, J = 15.8 Hz, 1H), 6.51 (d, J = 14.8 Hz, 1H), 4.57 (s, 1H), 3.57 (d, J = 8.8 Hz, 2H), 3.17 (s, 2H), 2.80 (t, J = 7.2 Hz, 1H) , 2.72 (t, J = 7.2 Hz, 4H), 2.33 (d, J = 1.6 Hz, 2H), 1.96 (m, 4H), 1.91 (s, 2H), 1.72 (m, 2H), 1.56 (m, 1H); MS (ESI): m/z (%) = 420.23 (100%) (M+1).
실시예-147
tert-부틸(E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-카르복실레이트
실시예 147은 유기 합성 분야의 당업자에게 공지된 통상적인 기술과 함께, 중간체-12를 사용하여 중간체-3a의 합성에 대해 설명된 절차에 따라 제조하였다.
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.47 (br s, 1H), 8.12 (s, 1H), 6.96 (s, 1H), 6.92 (d, J = 15.2 Hz, 1H), 6.70 (d, J = 15.2 Hz, 1H), 3.82 - 3.61 (m, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 6.8 Hz, 4H), 2.20 - 2.08 (m, 2H), 2.00 - 1.93 (m, 4H), 1.52 (s, 3H), 1.38 - 1.33 (m, 9H); MS (TOF): m/z (%) = 498.2359 (90%) (M+Na)+, 474.2308 (100%) (M-1).
실시예-148
(E)-2-(1,2-디메틸아제티딘-2-일)-N-((1,2,3,50,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.91 (s, 1H), 6.91 (s, 1H), 6.79(d, J = 14.8 Hz, 1H), 6.72 (d, J = 15.2 Hz, 1H), 3.33 - 3.16 (m, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.22 (s, 3H), 2.18 - 2.11 (m, 1H), 2.00 - 1.91 (m, 5H), 1.34 (s, 3H); MS (TOF): m/z (%) = 390.2279 (70%) (M+H)+, 388.2130 (100%) (M-1).
실시예-149
tert-부틸(S,E)-2-에틸-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ =10.38 (s, 1H), 8.0 (d, J = 4.4 Hz, 1H), 6.99 (s, 1H), 6.89 (d, J = 15.2 Hz, 1H), 6.50 (d, J= 15.2 Hz, 1H), 3.50 (m, 1H), 3.25 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H) , 2.65 (t, J = 7.2 Hz, 5H) , 1.95 (m, 4H), 1.77 (s, 3H), 1.80 (m, 4H), 1.58 (m, 1H), 1.36 (d, J =10 Hz, 9H), 0.81 (m, 3H); MS (ESI): m/z (%) = 502.23 (100%) (M-1).
실시예-150
tert-부틸(S,E)-2-(2-(N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ =7.95 (s, 1H), 7.42 (d, J = 15.2 Hz, 1H), 6.79 (d, J= 7.68 Hz, 1H), 6.55 (d, J = 15.2 Hz, 1H), 3.39 (m, 2H), 2.80 (q, J = 7.6 Hz, 4H) , 2.70 (t, J = 7.2 Hz, 5H) , 2.01 (m, 6H), 1.82 (m, 2H), 1.68 (m, 1H), 1.46 (d, J = 10 Hz, 3H), 1.38 (s, 3H), 1.32 (s, 7H); MS (ESI): m/z (%) = 488.24 (100%) (M-1).
실시예-151
(S,E)-2-(2-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트
1H NMR (400 MHz, DMSO-d 6 ): δ =9.19 (s, 1H), 90.6 (s, 1H), 8.39 (s, 1H), 7.56 (s, 1H), 7.11 (s, 1H), 6.97 (s, 1H), 6.84 (d, J = 15.6 Hz, 1H), 3.32 (s, 1H), 3.17 (s, 1H), 2.81 (t, J = 6.8 Hz, 4H ), 2.65 (t, J = 7.2 Hz, 4H ), 2.24 (m, 1H),1.96 (m, 6H), 1.83 (m, 4H), 0.85 (q, J = 6.8 Hz, 3H); MS (ESI): m/z (%) = 404.3 (100%) (M+1).
실시예-152
(S,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트
1H NMR (400 MHz, DMSO-d 6 ): δ =7.39 (s, 1H), 7.11 (d, J = 15.6 Hz, 1H), 7.02 (d, J = 15.6 Hz, 1H), 2.79 (q, J = 7.6 Hz, 5H ), 2.71 (t, J = 7.2 Hz, 4H ), 2.01 (m, 9H), 1.47 (q, J = 7.2 Hz, 3H ), 1.04 (d, J = 6.0 Hz, 2H); MS (ESI): m/z (%) = 390.24 (100%) (M+1).
실시예-153
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ =7.88 (s, 1H), 7.43 (s, 1H), 6.72 (d, J = 15.2 Hz, 1H), 6.62 (d, J= 15.2 Hz, 1H), 3.09 (q, J = 7.2 Hz, 4H) , 2.75 (m, 4H), 2.60 (t, J = 6.8 Hz, 4H) , 2.21 (s, 3H), 1.95 (m, 4H), 1.78 (t, J =10 Hz, 4H) , 1.17 (m, 8H); MS (ESI): m/z (%) = 404.30 (100%) (M+1).
실시예-154
tert-부틸(R,E)-2-(2-(N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.85 (s, 1H), 7.98 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.89 (q, J = 15.6 Hz, 1H), 6.58 (d, J = 15.2 Hz, 1H), 3.42 - 3.36 (m, 2H), 2.81 - 2.74 (m, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.21 - 1.94 (m, 5H), 1.88 - 1.75 (m, 2H), 1.72 - 1.66 (m, 1H), 1.48 (d, J = 9.6 Hz, 3H), 1.32 (s, 9H); MS (ESI): m/z (%) = 512.21 (40%) (M+Na)+; 502.28 (100%) (M-H)-.
실시예-155
(R,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 9.09 (bs, 2H), 8.21 (s, 1H), 7.39 (s, 1H), 7.13 (d, J = 15.6 Hz, 1H), 7.03 (d, J = 15.2 Hz, 1H), 2.81 - 2.64 (m, 10H), 2.10 - 1.89 (m, 9H), 1.48 (s, 3H); MS (ESI): m/z (%) = 390.18 (100%) (M-TFA)+.
실시예-156
(R,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (s, 1H), 7.44 (s, 1H), 6.75 (d, J = 15.6 Hz, 1H), 6.63 (d, J = 15.2 Hz, 1H), 2.90 - 2.88 (m, 4H), 2.80 (q, J = 7.2 Hz, 5H), 2.20 (s, 3H), 2.04 (quin, J = 7.2 Hz, 4H), 1.84 - 1.72 (m, 4H), 1.13 (s, 3H); MS (ESI): m/z (%) = 404.30 (100%) (M+H)+; 402.50 (100%) (M-1)-.
실시예-157
tert-부틸(R,E)-2-(3-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)알릴)-2-메틸피롤리딘-1-카르복실레이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.38 (s, 1H), 8.07 (d, J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.81 (q, J = 15.2 Hz, 1H), 6.64 (dd, J 1 = 8.0 Hz, J 2 = 15.2 Hz, 1H), 3.19 - 3.17 (m, 1H), 2.91 - 2.86 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 5H), 2.63 - 2.58 (m, 1H), 1.97 (quin, J = 7.2 Hz, 4H), 1.88 - 1.83 (m, 1H), 1.70 - 1.62 (m, 3H), 1.41 (d, J = 6.8 Hz, 9H), 1.30 (s, 3H); MS (ESI): m/z (%) = 526.28 (50%) (M+Na)+; 502.28 (100%) (M-H)-.
실시예-158
tert-부틸(R,E)-(2-(2-(3-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)알릴)-2-메틸피롤리딘-1-일)에틸)(메틸)카바메이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 10.37 (bs, 1H), 8.03 (s, 1H), 6.95 (s, 1H), 6.74 (d, J = 8.0 Hz, 2H), 3.12 (q, J = 7.2 Hz, 2H), 2.90 (bs, 1H), 2.80 (t, J = 7.2 Hz, 6H), 2.67 (t, J = 6.8 Hz, 5H), 2.29 - 2.26 (m, 2H), 1.96 (quin, J = 7.2 Hz, 4H), 1.68 - 1.67 (m, 4H), 1.38 (s, 12H), 1.28 (s, 3H); MS (ESI): m/z (%) = 560.31 (100%) (M+H)+; 559.29 (100%) (M-1)-.
실시예-159
(R,E)-3-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)프로프-1-엔-1-설폰아미드
1H NMR (400 MHz, DMSO-d 6 ): δ = 8.04 (s, 1H), 6.90 (s, 1H), 6.75 - 6.72 (m, 1H), 6.62 - 6.54 (m, 1H), 3.17 - 3.00 (m, 1H), 2.79 (t, J = 6.8 Hz, 5H), 2.69 (bs, 4H), 2.36 (s, 5H), 1.95 (t, J = 7.2 Hz, 4H), 1.81 - 1.74 (m, 3H), 1.58 (bs, 1H), 1.04 (s, 3H); MS (ESI): m/z (%) = 418.21 (100%) (M+H)+.
실시예-160
tert-부틸(S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)프로필)(메틸)카바메이트
1H NMR (400 MHz, DMSO-d 6 ): δ = 8.05 (s, 1H), 6.94 (s, 1H), 6.82 (d, J=15.2Hz, 1H), 6.62 - 6.57 (m, 1H), 3.26 - 3.22 (m, 1H), 3.30 - 2.94 (m, 1H), 2.82 - 2.65 (m, 13H), 2.20 - 2.18 (m, 2H), 2.03 - 1.92 (m, 5H), 1.77 - 1.71 (m, 3H), 1.59 - 1.48 (m, 3H), 1.40 - 1.37 (m, 9H); MS (ESI): m/z (%) = 547.5 (100%) (M+H)+.
실시예-161
tert-부틸 (E)-(3-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)프로필)(메틸)카바메이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.04 (s, 1H), 6.94 (s, 1H), 6.83 (d, J = 15.2 Hz, 1H), 6.77 (d, J = 15.2 Hz, 1H), 3.29 - 3.27 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 - 2.72 (m, 1H), 2.68 (t, J = 7.2 Hz, 4H), 2.50 (s, 3H), 2.37 - 2.33 (m, 2H), 2.08 - 2.06 (m, 1H), 2.00 - 1.92 (m, 4H), 1.58 - 1.49 (m, 2H), 1.39 - 1.37 (m, 9H), 1.32 (s, 3H), 1.28 - 1.22 (m, 1H); MS (ESI): m/z (%) = 547.5 (100%) (M+H)+, 545.7 (100%) (M-1).
실시예-162
tert-부틸(E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)에틸)(메틸)카바메이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.05 (s, 1H), 6.95 (s, 1H), 6.83 (d, J = 14.8 Hz, 1H), 6.75 - 6.68 (m, 1H), 3.32 - 3.23 (m, 1H), 3.09 - 3.02 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 - 2.71 (m, 2H), 2.67 (t, J = 7.2 Hz, 4H), 2.56 - 2.52 (m, 1H), 2.51 (s, 3H), 2.48 - 2.43 (m, 1H), 2.05 - 1.89 (m, 6H), 1.39 - 1.38 (m, 9H), 1.32 (s, 3H); MS (TOF): m/z (%) = 533.3222 (40%) (M+H)+, 531.3039 (100%) (M-1).
실시예-163
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(2-(메틸티오)에틸)아제티딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.36 (brs, 1H), 8.07 (s, 1H), 6.95 (s, 1H), 6.87 (d, J = 14.8 Hz, 1H), 6.83 (d, J = 14.8 Hz, 1H), 3.40 - 3.22 (m, 2H), 3.18 - 3.04 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.59 - 2.53 (m, 2H), 2.41- 2.38 (m, 2H), 2.08 - 1.88 (m, 8H), 1.32 (s, 3H); MS (TOF): m/z (%) = 450.1660 (100%) (M+H)+.
실시예-164
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(옥세탄-3-일)아제티딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.4 (brs, 1H), 8.13 (s, 1H), 6.96 (s, 1H), 6.84 (d, J = 15.2 Hz, 1H), 6.80 (d, J = 15.2 Hz, 1H), 4.56 (t, J = 6.0 Hz, 1H), 4.48 - 4.44 (m, 2H), 4.31 (t, J = 6.4 Hz, 1H), 3.93 - 3.87 (m, 1H), 3.38 - 3.28 (m, 3H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.12 - 2.06 (m, 1H), 2.01- 1.97 (m, 5H), 1.24 (s, 3H); MS (TOF): m/z (%) = 432.1744 (80%) (M+H)+.
실시예-165
tert-부틸(S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)메틸)-2-메틸피롤리딘-1-카르복실레이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.4 (brs, 1H), 8.10 (s, 1H), 6.98 - 6.93 (m, 2H), 6.74 (dd, J = 15.6 Hz, J = 5.2 Hz, 1H), 3.30 - 3.27 (m, 2H), 3.20 - 3.16 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 6.8 Hz, 4H), 2.04 - 1.91 (m, 7H), 1.75 - 1.46 (m, 3H), 1.39- 1.37 (m, 9H), 1.27 (s, 3H), 1.17 (s, 3H); MS (TOF): m/z (%) = 573.2813 (100%) (M+H)+;
실시예-166
tert-부틸(S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)메틸)-2-메틸피롤리딘-1-카르복실레이트
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.41 (brs, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.77 - 6.73 (m, 2H), 3.41 - 3.34 (m, 1H), 3.26 - 3.15 (m, 3H), 2.81 (t, J = 7.2 Hz, 4H), 2.57 (t, J = 7.2 Hz, 4H), 2.16 - 1.89 (m, 7H), 1.79 - 1.47 (m, 3H), 1.40 - 1.37 (m, 9H), 1.30 - 1.28 (m, 3H), 1.21 - 1.20 (m, 3H); MS (TOF): m/z (%) = 573.2814 (80%) (M+H)+;
실시예-167
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-설파모일에틸)피롤리딘-2-일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 10.42 (br s, 1H), 8.09 (s, 1H), 6.95 (s, 1H), 6.87 (d, J = 14.8 Hz, 1H), 6.75 (s, 2H), 6.66 (dd, J = 14.8 Hz, J = 7.2 Hz, 1H), 3.23 - 3.07 (m, 4H), 3.01 - 2.94 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.63 - 2.56 (m, 1H), 2.33- 2.27 (m, 1H), 2.02- 1.93 (m, 5H), 1.73 - 1.70 (m, 2H), 1.55 - 1.50 (m, 1H); MS (TOF): m/z (%) = 483.1490 (80%) (M+H)+.
실시예-168
(S,E)-2-(2-에틸-1-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1H NMR (400 MHz, DMSO-d6): δ =8.01 (s, 1H), 6.93 (s, 1H), 6.71 (d, J = 15.2 Hz, 1H), 6.58 (d, J= 15.6 Hz, 1H), 2.99 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H) , 2.66 (t, J = 7.2 Hz, 4H) , 2.57 (m, 1H), 2.24 (s, 3H), 1.95 (m, 4H), 1.85 (m, 1H), 1.72 (m, 4H), 1.45 (m, 1H), 0.8 (t, J =7.2 Hz, 3H); MS (ESI): m/z (%) = 418.19 (100%) (M+1);
실시예 - 169
(R,E)-2-(1-(부트-2-인-1-일)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드
1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.84 (s, 1H), 7.03 (d, J = 15.6 Hz, 1H), 6.91 (s, 1H), 6.35 - 6.23 (m, 1H), 4.31 - 4.03 (m, 3H), 3.26 - 3.07 (m, 2H), 2.82 - 2.67 (m, 8H), 2.20 - 2.05 (m, 1H), 1.97 - 1.83 (m, 6H), 1.74 - 1.61 (m, 4H); MS (TOF): m/z (%) = 428.1884 (100%) (M+H)+.
생물학적 활성:
시험관내(
In-vitro
) 분석:
THP1 단핵구를 PMA (100 ng/mL)로 분화시키고, 37℃에서 20시간 동안 5% CO2의 존재 하에 인큐베이션 하였다. 2 X105 분화된 세포를 96웰 조직 배양 플레이트의 웰당 플레이팅 하였다. 세포를 500 ng/mL 지질다당류를 사용하여 준비시키고, 동일한 조건 하에 4시간 동안 인큐베이션 하였다. 그 다음, 세포를 30분 동안 다양한 농도의 화합물로 처리한 후, 5 mM ATP로 1시간 동안 처리하였다. 상층액을 수집하고, IL-1b (Mabtech Cat # 3415-1H-20) 또는 TNF-a (Mabtech; Cat # 3510-1H-20) 검출 키트로 분석하였다. 데이터는 GraphPad Prism V7.0를 사용하여 분석하였다. 용량 반응 곡선 (Dose Response Curve, DRC)을 구축하여, 비선형 회귀 분석을 사용하여 GraphPad Prism에 백분율 세포 생존 데이터를 맞춰 IC50 값을 결정했다. 대표적인 화합물에 대한 시험관 내 IL-1β 억제 활성 (IC50)을 표 1에 나열하였다.
화합물 | IC50 (nM) |
실시예 4 | 7.4 |
실시예 8 | 10.7 |
실시예 10 | 64 |
실시예 13 | 9 |
실시예 14 | 17 |
실시예 21 | 2.4 |
실시예 23 | 14 |
실시예 56 | 8.8 |
실시예 63 | 8 |
실시예 71 | 87 |
실시예 84 | 8.5 |
실시예 90 | 16 |
실시예 91 | 2.9 |
실시예 100 | 70 |
실시예 105 | 61 |
실시예 111 | 4.3 |
실시예 125 | 16.4 |
실시예 127 | 5.6 |
실시예 129 | 5.9 |
실시예 131 | 16 |
실시예 139 | 21 |
실시예 144 | 8.6 |
실시예 147 | 11 |
실시예 149 | 11 |
실시예 153 | 32 |
생체 내(
In-vivo
) 효능 연구:
래트 마우스, 경구 투여 경로에서 시험 화합물의 생체 내(in vivo) 효능의 입증.
동물
모든 동물 실험은 사내에서 사육된 암컷 래트 및 마우스에서 수행되었다. 동물을 동물 사육장 조건 (25 ± 4 °C, 60-65 % 상대 습도, 12: 12 시간 명(light): 암(dark) 주기, 7.30 am에 빛이 켜짐)에 적응시키기 위해, 일주일 동안, 케이지당 6마리의 동물 그룹으로 동물을 수용했다. 모든 동물 실험은 '자이더스 연구 센터 동물 윤리 위원회'의 승인을 받아 국제적으로 유효한 가이드라인에 따라 수행하였다.
생체 내(
In-vivo
) LPS 및 ATP 유도 IL-1β 분석:
암컷 C57 마우스 (6-8주)는 PBS 중 50 μg/마우스의 지질다당류(LPS)를 복강내 주사했다. 동물을 시험 화합물 또는 비히클로 즉시 처리했다. LPS 주사 2시간 후, 동물에게 복강내 경로를 통해 PBS에 용해된 12.5 mg/마우스의 ATP를 투여하였다. ATP 주사 30분 후, ELISA에 의해 IL-1β 추정을 위해 혈청을 수집하였다.
본 발명의 신규 화합물들은 잘 알려진 바와 같은 기술 및 공정 및 농도에 의해 적합한 부형제와 조합함으로써 적합한 약학적으로 허용가능한 조성물로 제형화될수 있다.
일부 시험 화합물의 대표적인 데이터를 표 2에 나열하였다:
화합물 (용량 10 mpk, po) | LPS+ATP 챌린지된 C57 마우스에서 % IL-1β 억제 |
실시예 4 | 90% |
실시예 5 | 70% |
실시예 22 | 83% |
실시예 40 | 86% |
실시예 55 | 82.5% |
실시예 69 | 84% |
실시예 73 | 80% |
실시예 77 | 47% |
실시예 101 | 82% |
실시예 102 | 74% |
식 (I)의 화합물 또는 이를 함유하는 약학적 조성물은 NLRP3 활성의 억제를 위한 약제로서 유용하고 인간 및 기타 온혈 동물에 적합하며, 경구, 국소 또는 비경구 투여에 의해 투여될 수 있다.
따라서, 본 발명의 화합물을 포함하는 약학적 조성물은 필요에 따라 적합한 결합제, 적합한 증량제 및/또는 희석제 및 임의의 기타 적합한 제제를 포함할 수 있다. 선택적으로, 약학적 조성물은 적합한 코팅제로 적절하게 코팅될 수 있다.
본 발명의 화합물 (I)은 NLRP3 억제제이고, NLRP3에 의해 매개되는 질병 상태, 바람직하게는 인터루킨 1β 활성이 연루된 질병 또는 상태 및 관련 장애의 치료에 유용하다.
약학적 조성물 및 이의 단위 투여량 형태에서, 활성 성분, 즉 본 발명에 따른 식 (I)의 화합물의 양은 특정 적용 방법, 특정 화합물의 효능 및 원하는 농도에 따라 광범위하게 변경되거나 조정될 수 있다. 일반적으로, 활성 성분의 양은 조성물의 중량을 기준으로 0.5% 내지 90% 범위일 것이다.
식 (I)의 본 발명의 화합물은 단독으로 또는 숙련된 의사가 쉽게 확인할 수 있는 하나 이상의 다른 치료제와 임의의 조합으로 사용될 수 있다. 이러한 다른 치료제는 치료되는 질병의 유형, 중증도, 환자가 복용하는 기타 약물 등에 따라 선택될 수 있다. 따라서 예를 들어, 류마티스 관절염의 치료를 위해, 하나 이상의 DMARD가 본 발명의 화합물과 조합으로 사용될 수 있다.
하나의 구체예에서 본 발명의 식 (I)의 화합물은 하기 치료제로부터 선택되는 하나 이상의 적합한 약학적 활성제와 임의의 조합으로 조합하여 사용될 수 있다. 인터루킨-1β 의 억제제(예: 릴로나셉트, 카나키누맙, 및 아나킨라); 면역 억제제(예: 메토트렉세이트, 메르캅토퓨린, 시클로포스파미드), 대사 장애 약물, 글루코코르티코이드, 비스테로이드성 항염증 약물, Cox-2 특이적 억제제, TNF-α 결합 단백질 (예: 인플릭시맙, 에타너셉트), 인터페론-13, 인터페론, 인터루킨-2, 항히스타민제, 베타-작용제, BTK 억제제, 항콜린제, 항암제 또는 이들의 적합한 약학적으로 허용가능한 염. 조합하여 사용하기 위한 추가적인 예는 비알코올성 지방간염 (Non-Alcoholic Steato- Hepatitis, NASH) 및 섬유증 약물, 항암성 항생제, 호르몬, 아로마타제 억제제, 항체, 사이토카인, 백신, 약물 접합체, 미토겐 활성화 단백질 키나제 신호전달의 억제제(예: BAY 43-9006), Syk 억제제, mTOR 억제제, 항체 (리툭산), 및 BCR/ABL 길항제.
본 발명이 그 특정 구체예에 관하여 설명되었지만, 특정 수정 및 균등물은 당업자에게 명백할 것이며, 본 발명의 범위 내에 포함되는 것으로 의도된다.
Claims (17)
- 일반식 (I)의 구조를 갖는 화합물,
식 (I)
이의 호변이성질체 형태, 이의 입체이성질체, 이의 거울상이성질체, 이의 약학적으로 허용가능한 염, 및 이들을 함유하는 약학적 조성물로서, 여기에서,
R1은 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 시아노, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C2-C6)알케닐, (C1-C6)알콕시, (C3-C7)시클로알킬, NH2, NH(C1-C6)알킬, N(C3-C7)시클로알킬, N(C1-C6 알킬)2, 아릴, 헤테로아릴, 헤테로시클릴, 벤질, 티올, 메르캅토 알킬, SO2(C1-C6)알킬, (C1-C6)티오-알콕시, 아미드로부터 선택된 기로부터 선택되고;
X는 N-R5; O, S, SO2이고;
R5는 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 시아노, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C2-C6)알케닐, (C2-C6)알키닐, (C1-C6)알콕시, (C3-C7)시클로알킬, (C1-C6)알킬SO2(C1-C6)알킬, (C1-C6)알킬N(C1-C6)알킬, (C1-C6)알킬N(C3-C7)시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴, 벤질, tert-부틸옥시카르보닐, 티올, 메르캅토알킬, SO2(C1-C6)알킬, SO2(C3-C7)시클로알킬, SO2-아릴, SO2-헤테로시클릴, (C1-C6)티오알킬, (C1-C6)티오알콕시, (C1-C6)알킬SO2NH2, -CONH2, -CO(C1-C6)알킬, -CO(C1-C6)할로알킬, -CO-아릴, -CO-헤테로아릴, -CO-헤테로시클릴, 4- 내지 7-원 헤테로시클릭 고리, 7- 내지 14-원 바이시클릭 헤테로시클릭 고리 시스템, 선택적으로 하나 이상의 헤테로원자를 갖는 가교 또는 스피로 고리 시스템으로부터 선택된 기로부터 선택되고;
m 및 n은 독립적으로 정수 0 내지 3으로부터 선택되고;
q 및 r은 독립적으로 정수 1 내지 4로부터 선택되고;
R2는 각 경우에 독립적으로 수소, 할로겐, 시아노, 선택적으로 치환된 (C1-C6)알킬, (C2-C6)알케닐, (C1-C6)알콕시, (C3-C7)시클로알킬, 벤질, 아릴, 헤테로아릴, 헤테로시클릴, 티올, 티오알킬, 티오-알콕시, SO2(C1-C6)알킬, SO(C1-C6)알킬, 선택적으로 하나 이상의 헤테로원자를 갖는 가교 또는 스피로 고리 시스템으로부터 선택된 기로부터 선택되고;
각각의 R3 및 R4는 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 시아노, 니트로, 아미드, 설폰아미드, 아실, 히드록실, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C3-C6)시클로알킬, (C1-C6)알콕시, SO2(C1-C6)알킬, 티올, 메르캅토 알킬, 벤질, 아릴, 헤테로아릴, 헤테로시클릴로부터 선택된 기로부터 선택되고; 대안적으로 R3 및 R4는 결합을 형성하고;
'B'는 하기 고리 시스템으로부터 선택되고,
여기에서 X, Y, Z는 각 경우에 독립적으로 C, N, S, SO2 및 O로부터 선택되며, 이는, 가능한 경우 선택적으로 치환될 수 있고,
각각의 R6, R7, R8, R9 , R10 및 R11는 각 경우에 독립적으로 수소, 할로겐, 시아노, 아미드, 설폰아미드, 아실, 히드록실, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬, (C3-C6)시클로알킬, (C1-C6)알콕시, 벤질, 아릴, 헤테로아릴, 헤테로시클릴로부터 선택된 기로부터 선택되며; 대안적으로 각각의 R7 및 R8 , R8 및 R9, R9 및 R10 또는 R10 및 R11는 가능한 경우, N, O, 및 S(O)p로 구성된 군으로부터 선택된 0 내지 2개의 추가 헤테로원자를 함유하는 4 내지 7원 포화 또는 부분 포화 고리를 함께 형성할 수 있고; p = 1 내지 2이다. - 청구항 1에 있어서, R1은 각 경우에 수소, 할로겐, 할로알킬, 선택적으로 치환된 (C1-C6)알킬로부터 선택된 기로부터 선택되는 것인 화합물.
- 청구항 1에 있어서, R2는 각 경우에 수소, 할로겐, 할로알킬, 선택적으로 치환된 (C1-C6)알킬로부터 선택된 기로부터 선택되는 것인 화합물.
- 청구항 1에 있어서, R3 및 R4는 각 경우에 독립적으로 수소, 할로겐, 할로알킬, 선택적으로 치환된 (C1-C6)알킬로부터 선택된 기로부터 선택되는 것인 화합물.
- 청구항 1에 있어서, 각각의 R6, R7, R8, R9 , R10 및 R11은 각 경우에 독립적으로 수소, 할로겐, 선택적으로 치환된 (C1-C6)알킬, (C1-C6)할로알킬로부터 선택된 기로부터 선택되는 것인 화합물.
- 선행하는 청구항 중 어느 한 항에 있어서, 상기 기 중 어느 기가 치환되는 경우, 치환기는 수소, 히드록시, 시아노, 할로, 할로알킬, 할로알킬옥시, 알킬티오 (C1-C6)알킬, (C2-C6)알케닐, (C2-C6)알키닐, (C3-C7)시클로알킬, C1-C6 알콕시, 아릴, 헤테로시클릴, 헤테로아릴, -COR12, -CSR12, C(O)OR12, C(O)-R12, -C(O)-NR12R13, -C(S)-NR12R13, -SO2R12 기로부터 선택되며, 여기에서 각각의 R12 및 R13은 독립적으로 수소, 선택적으로 치환된 (C1-C6)알킬, (C2-C6)알케닐, (C2-C6)알키닐, (C3-C7)시클로알킬, 아릴, 헤테로아릴, 헤테로시클릴 기로부터 선택된 기로부터 선택되는 것인 화합물.
- 청구항 1에 있어서, 하기를 포함하는 군으로부터 선택되는 것인 화합물:
(R,E)-2-(1-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드;
(S,E)-2-(1-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-프로필피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-(시클로프로필메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)-피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-아세틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐-1-설폰아미드;
(E)-2-(1-벤질피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에탄설폰아미드;
tert-부틸(R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일) 설파모일)-비닐)피롤리딘-1-카르복실레이트;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-메톡시에틸)피롤리딘-2-일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(이소프로필설포닐)피롤리딘-2-일)에텐설폰아미드;
(R,E)-2-(1-((3-플루오로페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(피라진-2-카르보닐)피롤리딘-2-일)에텐설폰아미드;
(R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복스아미드;
(R,E)-2-(1-(시클로프로판카르보닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2,2,2-트리플루오로아세틸)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-(메틸티오)에틸)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2,2,2-트리플루오로에틸)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소부틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-(에틸설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소프로필피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(3-(메틸설포닐)프로필)피롤리딘-2-일)에텐설폰아미드;
(R,E)-2-(1-벤조일피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(R,E)-N-((2-(1-벤조일피롤리딘-2-일)비닐)설포닐)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)벤즈아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티오펜-3-카르보닐)피롤리딘-2-일)에텐설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 메탄 설포네이트;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드 말리에이트;
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-3-(피롤리딘-2-일)프로프-1-엔-1-설폰아미드;
(R,E)-2-(1-(시클로헥실설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-2-(1-(시클로헥실메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-시클로헥실피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(1-메틸피페리딘-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,Z)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소프로필피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(옥세탄-3-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-티오피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티아졸-2-일메틸)피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-4-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피페리딘-4-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피페리딘-4-일)에텐설폰아미드;
(E)-2-(1-아세틸피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드;
tert-부틸 (E)-4-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일) 설파모일)비닐)-피페리딘-1-카르복실레이트;
(E)-2-(1-에틸피페리딘-4-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-에틸피롤리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐설폰아미드;
(R,E)-1,1-디에틸-3-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)피롤리딘-1-이움브로마이드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-3-일)에텐-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (R,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일) 설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-2-(1-아세틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-1,1-디에틸-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)-비닐)-2-메틸피롤리딘-1-이움 브로마이드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(메틸설포닐)-피롤리딘-2-일)에텐-1-설폰아미드;:
(R,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-에틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-(시클로프로필메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐설폰아미드;
(S,E)-tert-부틸2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일) 설파모일) 비닐)피롤리딘-1-카르복실레이트;
(S,E)-2-(1-(시클로프로필메틸)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(피리딘-3-일설포닐)-피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-에틸피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-(메틸설포닐) 피롤리딘-2-일)에텐-설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐설폰아미드;
(S,E)-2-(1-아세틸피롤리딘-2-일)-N-((2,6-디이소프로필페닐) 카르바모일)에텐설폰아미드;
(S,E)-2-(1-아세틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-카르보닐)피롤리딘-2-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(테트라히드로-2H-피란-4-일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-니코티노일피롤리딘-2-일)에텐설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(테트라히드로퓨란-2-일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티오펜-2-일메틸)-피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸(S,E)-2-(2-(N-((4-플루오로-2,6-디이소프로필페닐)카르바모일) 설파모일) 비닐)-피롤리딘-1-카르복실레이트;
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(1-메틸피롤리딘-2-일) 에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-이소부틸-2-메틸-피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-프로필피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(티아졸-2-일)피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-3-일)에텐-설폰아미드;
(E)-2-(1-에틸피페리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드;
(E)-tert-부틸 3-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일) 설파모일)비닐)-피페리딘-1-카르복실레이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1- (메틸설포닐) 피페리딘-3-일)에텐설폰아미드;
(E)-2-(1-아세틸피페리딘-3-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-설폰아미드;
tert-부틸(E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-아제티딘-1-카르복실레이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸아제티딘-2-일)에텐-1-설폰아미드;
(E)-2-(아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(테트라히드로-2H-피란-4-일)피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(1-((5-클로로티오펜-2-일)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-(벤질설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-((4-메톡시페닐)설포닐) 피롤리딘-2-일)에텐설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-((4-플루오로페닐)설포닐) 피롤리딘-2-일)에텐설폰아미드;
(S,E)-2-(1-((2-시아노페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-(시클로헥실설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-(4-플루오로벤질)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐설폰아미드;
(S,E)-2-(1-((4-시아노페닐)설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(4-시아노벤질)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(피페리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-메틸피페리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(1-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(1-(메틸설포닐)피롤리딘-2-일)에텐-1-설폰아미드;
((E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-3-(피페리딘-2-일)프로프-1-엔-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(인돌린-2-일)에텐-1-설폰아미드;
tert-부틸(E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일) 설파모일) 비닐)인돌린-1-카르복실레이트;
((S,E)-2-(1-(시클로프로필메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(시클로프로필설포닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (S,E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일) 설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
tert-부틸 (R,E)-2-(2-(N-((2,6-디이소프로필페닐)카르바모일) 설파모일) 비닐)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(R,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1,2-디메틸피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(1-에틸-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
비스 소듐 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
소듐 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
tert-부틸 (S,E)-2-(2-(N-((2,6-디이소프로필페닐)카르바모일)설파모일) 비닐)-2-메틸피롤리딘-1-카르복실레이트;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1,2-디메틸피롤리딘-2-일)에텐-1-설폰아미드;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(옥세탄-3-일)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (S,E)-2-(2-(N-((4-플루오로-2,6-디이소프로필페닐)카르바모일) 설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(S,E)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세티이트;
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((4-플루오로-2,6-디이소프로필페닐)카르바모일)에텐-1-설폰아미드;
(E)-2-(1-아세틸아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)에틸)(메틸)카바메이트;
(S,E)-2-(1-알릴피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(1H-벤조[d]이미다졸-6-카르보닐)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-2-(1-(시클로프로필설포닐)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(4-메톡시벤질)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일) 카르바모일)설파모일)비닐)피롤리딘-1-일)헥사히드로시클로펜타[c]피롤-2(1H)-카르복실레이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-((2R)-1-(옥타히드로시클로-펜타[c]피롤-5-일)피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(E)-2-(1-(시클로프로필설포닐)아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(S,E)-N-((2,6-디이소프로필페닐)카르바모일)-2-(1-(티아졸-2-일)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-일)에틸)(메틸)카바메이트;
포타슘 (R,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
tert-부틸 (E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)아제티딘-1-일)에틸)(메틸)카바메이트;
(S,E)-2-(1-(시클로헥실메틸)-2-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
소듐 (R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-(테트라히드로-2H-티오피란-4-일)피롤리딘-2-일)비닐)설포닐)아미드;
소듐 (R,E)-((2-(1-시클로헥실피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
소듐 (S,E)-((2,6-디이소프로필페닐)카르바모일)((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)아미드;
소듐 (R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-메틸피롤리딘-2-일)비닐)설포닐)아미드;
포타슘 (R,E)-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)((2-(1-메틸피롤리딘-2-일)비닐)설포닐)아미드;
소듐 (S,E)-((2-(1,2-디메틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
소듐 (S,E)-((2-(1-에틸피롤리딘-2-일)비닐)설포닐)((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)아미드;
(S,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-히드록시에틸)피롤리딘-2-일)에텐-1-설폰아미드;
tert-부틸 (E)-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-카르복실레이트;
(E)-2-(1,2-디메틸아제티딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (S,E)-2-에틸-2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-카르복실레이트;
tert-부틸 (S,E)-2-(2-(N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(S,E)-2-(2-에틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(S,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(S,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (R,E)-2-(2-(N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)-2-(2-메틸피롤리딘-2-일)에텐-1-설폰아미드 2,2,2-트리플루오로아세테이트;
(R,E)-2-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,6,7,8-헥사히드로-as-인다센-4-일)카르바모일)에텐-1-설폰아미드;
tert-부틸 (R,E)-2-(3-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)알릴)-2-메틸피롤리딘-1-카르복실레이트;
tert-부틸 (R,E)-(2-(2-(3-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)알릴)-2-메틸피롤리딘-1-일)에틸)(메틸)카바메이트;
(R,E)-3-(1,2-디메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)프로프-1-엔-1-설폰아미드;
tert-부틸 (S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)피롤리딘-1-일)프로필)(메틸)카바메이트;
tert-부틸 (E)-(3-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)프로필)(메틸)카바메이트;
tert-부틸 (E)-(2-(2-(2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)에틸)(메틸)카바메이트;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(2-(메틸티오)에틸)아제티딘-2-일)에텐-1-설폰아미드;
(E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(2-메틸-1-(옥세탄-3-일)아제티딘-2-일)에텐-1-설폰아미드;
tert-부틸 (S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)메틸)-2-메틸피롤리딘-1-카르복실레이트;
tert-부틸 (S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)설파모일)비닐)-2-메틸아제티딘-1-일)메틸)-2-메틸피롤리딘-1-카르복실레이트;
(R,E)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)-2-(1-(2-설파모일에틸)피롤리딘-2-일)에텐-1-설폰아미드;
(S,E)-2-(2-에틸-1-메틸피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-일)카르바모일)에텐-1-설폰아미드;
(R,E)-2-(1-(부트-2-인-1-일)피롤리딘-2-일)-N-((1,2,3,5,6,7-헥사히드로-s-인다센-4-yl)카르바모일)에텐-1-설폰아미드; - 치료적 유효량의 선행하는 청구항 중 어느 항에 따른 식 (I)의 화합물, 및 선택적으로 하나 이상의 약학적으로 허용가능한 담체, 희석제 또는 부형제를 포함하는 약학적 조성물.
- 인터루킨 1β 활성 및 인터루킨-18 (IL-18)이 연루된 질병 또는 상태의 치료 뿐만 아니라 NLRP3 조절제에 의해 치료되는 질병의 치료 방법으로서, 이를 필요로 하는 개체에게 유효량의 선행하는 청구항 중 어느 항에 따른 식 (I)의 화합물 또는 이의 적합한 약학적 조성물을 투여하는 단계를 포함하는 것인 방법.
- NLRP3 조절제가 병태생리학적 기능을 갖는 질병의 치료에 적합한, 선행하는 청구항 중 어느 항에 따른 식 (I)의 화합물 또는 이의 약학적 조성물의 용도.
- 청구항 8에 있어서, 하나 이상의 적합한 약학적 활성제와 조합되고,
상기 하나 이상의 적합한 약학적 활성제는 인터루킨-1β의 억제제; 면역 억제제; 대사 장애 약물, 글루코코르티코이드, 비스테로이드성 항염증 약물, COX-2 특이적 억제제, 항염증 약물, TNF-α 결합 단백질, 인터페론-13, 인터페론, 인터루킨-2, 항히스타민제, 베타-작용제, BTK 억제제, 항콜린제, 항암제 또는 이들의 적합한 약학적으로 허용가능한 염, 비알코올성 지방간염(Non-Alcoholic Steato- Hepatitis, NASH) 및 섬유증 약물, 항암 약물, 항생제, 호르몬, 아로마타제 억제제, 미토겐 활성화 단백질 키나제 신호전달의 억제제, Syk 억제제, mTOR 억제제, 및 BCR/ABL 길항제로부터 선택되는 것인, 약학적 조성물. - 하기 단계를 포함하는 청구항 1에 따른 식 (I)의 화합물을 제조하는 방법:
(a) (i) 식 (12)의 화합물을 식 (3)의 화합물과 반응시켜 식 (13)의 화합물을 얻는 단계로서, 여기에서 모든 기호는 청구항 1에서 정의된 바와 같은 것인 단계,
(ii) 식 (13)의 화합물을 DMSO와 반응시켜 식 (14)의 화합물을 얻는 단계로서, 여기에서 모든 기호는 청구항 1에서 정의된 바와 같은 것인 단계,
(iii) 식 (14)의 화합물을 식 (7)의 화합물의 이소시아나토 유도체와 반응시켜 식 (I)의 화합물을 얻는 단계로서, 여기에서 모든 기호는 청구항 1에서 정의된 바와 같은 것인 단계,
(b) (i) 식 (15)의 화합물을 식 (7)의 화합물의 이소시아나토 유도체와 반응시켜 식 (16)의 화합물을 얻는 단계로서, 여기에서 모든 기호는 청구항 1에서 정의된 바와 같은 것인 단계,
(ii) 식 (16)의 화합물을 식 (4)의 화합물과 반응시켜 식 (I)의 화합물을 얻는 단계로서, 여기에서 모든 기호는 청구항 1에서 정의된 바와 같은 것인 단계
.
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